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Drug and Vaccine Development for the Treatment and Prevention of Urinary Tract Infections

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  • Authors: Valerie P. O’Brien1, Thomas J. Hannan2, Hailyn V. Nielsen3, Scott J. Hultgren4
  • Editors: Matthew A. Mulvey5, Ann E. Stapleton6, David J. Klumpp7
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: >Department of Molecular Microbiology, Center for Women’s Infectious Disease Research; 2: Department of Pathology & Immunology, Washington University Medical School, St. Louis, MO 63110; 3: Department of Molecular Microbiology, Center for Women’s Infectious Disease Research; 4: Department of Molecular Microbiology, Center for Women’s Infectious Disease Research; 5: University of Utah, Salt Lake City, UT; 6: University of Washington, Seattle, WA; 7: Northwestern University, Chicago, IL
  • Source: microbiolspec February 2016 vol. 4 no. 1 doi:10.1128/microbiolspec.UTI-0013-2012
  • Received 17 August 2012 Accepted 23 March 2015 Published 05 February 2016
  • Scott J. Hultgren, hultgren@wusm.wustl.edu
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  • Abstract:

    Urinary tract infections (UTI) are among the most common bacterial infections in humans, affecting millions of people every year. UTI cause significant morbidity in women throughout their lifespan, in infant boys, in older men, in individuals with underlying urinary tract abnormalities, and in those that require long-term urethral catheterization, such as patients with spinal cord injuries or incapacitated individuals living in nursing homes. Serious sequelae include frequent recurrences, pyelonephritis with sepsis, renal damage in young children, pre-term birth, and complications of frequent antimicrobial use including high-level antibiotic resistance and colitis. Uropathogenic (UPEC) cause the vast majority of UTI, but less common pathogens such as and other enterococci frequently take advantage of an abnormal or catheterized urinary tract to cause opportunistic infections. While antibiotic therapy has historically been very successful in controlling UTI, the high rate of recurrence remains a major problem, and many individuals suffer from chronically recurring UTI, requiring long-term prophylactic antibiotic regimens to prevent recurrent UTI. Furthermore, the global emergence of multi-drug resistant UPEC in the past ten years spotlights the need for alternative therapeutic and preventative strategies to combat UTI, including anti-infective drug therapies and vaccines. In this chapter, we review recent advances in the field of UTI pathogenesis, with an emphasis on the identification of promising drug and vaccine targets. We then discuss the development of new UTI drugs and vaccines, highlighting the challenges these approaches face and the need for a greater understanding of urinary tract mucosal immunity.

  • Citation: O’Brien V, Hannan T, Nielsen H, Hultgren S. 2016. Drug and Vaccine Development for the Treatment and Prevention of Urinary Tract Infections. Microbiol Spectrum 4(1):UTI-0013-2012. doi:10.1128/microbiolspec.UTI-0013-2012.

References

1. Griebling TL. 2005. Urologic diseases in America project: trends in resource use for urinary tract infections in women. J Urol 173:1281–1287. [PubMed][CrossRef]
2. Foxman B. 2014. Urinary tract infection syndromes: occurrence, recurrence, bacteriology, risk factors, and disease burden. Infect Dis Clin North Am 28:1–13. [PubMed][CrossRef]
3. Foxman B. 2002. Epidemiology of urinary tract infections: incidence, morbidity, and economic costs. Am J Med 113(Suppl 1A):5S–13S. [PubMed][CrossRef]
4. Foxman B, Barlow R, D’Arcy H, Gillespie B, Sobel JD. 2000. Urinary tract infection: self-reported incidence and associated costs. Ann Epidemiol 10:509–515. [PubMed][CrossRef]
5. Hooton TM, Stamm WE. 1997. Diagnosis and treatment of uncomplicated urinary tract infection. Infect Dis Clinics North Am 11:551–581. [PubMed][CrossRef]
6. Celik O, Ipekci T, Aydogdu O, Yucel S. 2014. Current medical diagnosis and management of vesicoureteral reflux in children. Nephrourol Mon 6:e13534. [PubMed]
7. Foxman B. 1990. Recurring urinary tract infection: incidence and risk factors. Am J Public Health 80:331–333. [PubMed][CrossRef]
8. Nuutinen M, Uhari M. 2001. Recurrence and follow-up after urinary tract infection under the age of 1 year. Pediatr Nephrol 16:69–72. [PubMed][CrossRef]
9. Scholes D, Hooton TM, Roberts PL, Stapleton AE, Gupta K, Stamm WE. 2000. Risk factors for recurrent urinary tract infection in young women. J Infect Dis 182:1177–1182. [PubMed][CrossRef]
10. Hawn TR, Scholes D, Li SS, Wang H, Yang Y, Roberts PL, Stapleton AE, Janer M, Aderem A, Stamm WE, Zhao LP, Hooton TM. 2009. Toll-like receptor polymorphisms and susceptibility to urinary tract infections in adult women. PLoS One 4:e5990. [PubMed][CrossRef]
11. Ronald A. 2002. The etiology of urinary tract infection: traditional and emerging pathogens. Am J Med 113(Suppl 1A):14S–19S. [PubMed][CrossRef]
12. Sedor J, Mulholland SG. 1999. Hospital-acquired urinary tract infections associated with the indwelling catheter. Urol Clin North Am 26:821–828. [PubMed][CrossRef]
13. Edwards JR, Peterson KD, Mu Y, Banerjee S, Allen-Bridson K, Morrell G, Dudeck MA, Pollock DA, Horan TC. 2009. National Healthcare Safety Network (NHSN) report: data summary for 2006 through 2008, issued December 2009. Am J Infect Control 37:783–805. [PubMed][CrossRef]
14. Hidron AI, Edwards JR, Patel J, Horan TC, Sievert DM, Pollock DA, Fridkin SK. 2008. NHSN annual update: antimicrobial-resistant pathogens associated with healthcare-associated infections: annual summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2006-2007. Infect Control Hosp Epidemiol 29:996–1011. [PubMed][CrossRef]
15. Lo E, Nicolle L, Classen D, Arias KM, Podgorny K, Anderson DJ, Burstin H, Calfee DP, Coffin SE, Dubberke ER, Fraser V, Gerding DN, Griffin FA, Gross P, Kaye KS, Klompas M, Marschall J, Mermel LA, Pegues DA, Perl TM, Saint S, Salgado CD, Weinstein RA, Wise R, Yokoe DS. 2008. Strategies to prevent catheter-associated urinary tract infections in acute care hospitals. Infect Control Hosp Epidemiol 29(Suppl 1):S41–50. [PubMed][CrossRef]
16. Warren JW, Damron D, Tenney JH, Hoopes JM, Deforge B, Muncie HL, Jr. 1987. Fever, bacteremia, and death as complications of bacteriuria in women with long-term urethral catheters. J Infect Dis 155:1151–1158. [PubMed][CrossRef]
17. Wagenlehner FM, Cek M, Naber KG, Kiyota H, Bjerklund-Johansen TE. 2012. Epidemiology, treatment and prevention of healthcare-associated urinary tract infections. World J Urol 30:59–67. [PubMed][CrossRef]
18. Raz R, Gennesin Y, Wasser J, Stoler Z, Rosenfeld S, Rottensterich E, Stamm WE. 2000. Recurrent urinary tract infections in postmenopausal women. Clin Infect Dis 30:152–156. [PubMed][CrossRef]
19. Rogers BA, Sidjabat HE, Paterson DL. 2011. Escherichia coli O25b-ST131: a pandemic, multiresistant, community-associated strain. J Antimicrob Chemother 66:1–14. [PubMed][CrossRef]
20. Weyrauch HM, Rosenberg ML, Amar AD, Redor M. 1957. Effects of antibiotics and vaccination on experimental pyelonephritis. J Urol 78:532–539. [PubMed]
21. van der Starre WE, van Nieuwkoop C, Paltansing S, van’t Wout JW, Groeneveld GH, Becker MJ, Koster T, Wattel-Louis GH, Delfos NM, Ablij HC, Leyten EM, Blom JW, van Dissel JT. 2010. Risk factors for fluoroquinolone-resistant Escherichia coli in adults with community-onset febrile urinary tract infection. J Antimicrob Chemother 66:650–656. [PubMed][CrossRef]
22. Taneja N, Rao P, Arora J, Dogra A. 2008. Occurrence of ESBL & Amp-C beta-lactamases & susceptibility to newer antimicrobial agents in complicated UTI. Indian J Med Res 127:85–88. [PubMed]
23. Nicolas-Chanoine MH, Blanco J, Leflon-Guibout V, Demarty R, Alonso MP, Canica MM, Park YJ, Lavigne JP, Pitout J, Johnson JR. 2008. Intercontinental emergence of Escherichia coli clone O25:H4-ST131 producing CTX-M-15. J Antimicrob Chemother 61:273–281. [PubMed][CrossRef]
24. Totsika M, Beatson SA, Sarkar S, Phan MD, Petty NK, Bachmann N, Szubert M, Sidjabat HE, Paterson DL, Upton M, Schembri MA. 2011. Insights into a multidrug resistant Escherichia coli pathogen of the globally disseminated ST131 lineage: genome analysis and virulence mechanisms. PLoS One 6:e26578. [PubMed][CrossRef]
25. Foxman B. 2010. The epidemiology of urinary tract infection. Nat Rev Urol 7:653–660. [PubMed][CrossRef]
26. Aldeyab MA, Kearney MP, Scott MG, Aldiab MA, Alahmadi YM, Darwish Elhajji FW, Magee FA, McElnay JC. 2012. An evaluation of the impact of antibiotic stewardship on reducing the use of high-risk antibiotics and its effect on the incidence of Clostridium difficile infection in hospital settings. J Antimicrob Chemother doi:dks330 [pii] 10.1093/jac/dks330. [PubMed][CrossRef]
27. Mulvey MA, Lopez-Boado YS, Wilson CL, Roth R, Parks WC, Heuser J, Hultgren SJ. 1998. Induction and evasion of host defenses by type 1-piliated uropathogenic Escherichia coli. Science 282:1494–1497. [PubMed][CrossRef]
28. Schwartz DJ, Chen SL, Hultgren SJ, Seed PC. 2011. Population dynamics and niche distribution of uropathogenic Escherichia coli during acute and chronic urinary tract infection. Infect Immun 79:4250–4259. [PubMed][CrossRef]
29. Anderson GG, Palermo JJ, Schilling JD, Roth R, Heuser J, Hultgren SJ. 2003. Intracellular bacterial biofilm-like pods in urinary tract infections. Science 301:105–107. [PubMed][CrossRef]
30. Justice SS, Hung C, Theriot JA, Fletcher DA, Anderson GG, Footer MJ, Hultgren SJ. 2004. Differentiation and developmental pathways of uropathogenic Escherichia coli in urinary tract pathogenesis. Proc Natl Acad Sci U S A 101:1333–1338. [PubMed][CrossRef]
31. Rosen DA, Hooton TM, Stamm WE, Humphrey PA, Hultgren SJ. 2007. Detection of intracellular bacterial communities in human urinary tract infection. PLoS Med 4:e329. [PubMed][CrossRef]
32. Robino L, Scavone P, Araujo L, Algorta G, Zunino P, Vignoli R. 2013. Detection of intracellular bacterial communities in a child with Escherichia coli recurrent urinary tract infections. Pathog Dis 68:78–81. [PubMed][CrossRef]
33. Robino L, Scavone P, Araujo L, Algorta G, Zunino P, Pirez MC, Vignoli R. 2014. Intracellular bacteria in the pathogenesis of Escherichia coli urinary tract infection in children. Clin Infect Dis 59:e158–164. [PubMed][CrossRef]
34. Hung CS, Dodson KW, Hultgren SJ. 2009. A murine model of urinary tract infection. Nat Protoc 4:1230–1243. [PubMed][CrossRef]
35. O’Brien VP, Hannan TJ, Schaeffer AJ, Hultgren SJ. 2015. Are you experienced? Understanding bladder innate immunity in the context of recurrent urinary tract infection. Curr Opin Infect Dis 28:97–105. [PubMed][CrossRef]
36. Connell I, Agace W, Klemm P, Schembri M, Marild S, Svanborg C. 1996. Type 1 fimbrial expression enhances Escherichia coli virulence for the urinary tract. Proc Natl Acad Sci U S A 93:9827–9832. [PubMed][CrossRef]
37. O’Hanley P, Lark D, Falkow S, Schoolnik G. 1985. Molecular basis of Escherichia coli colonization of the upper urinary tract in BALB/c mice. Gal-Gal pili immunization prevents Escherichia coli pyelonephritis in the BALB/c mouse model of human pyelonephritis. J Clin Invest 75:347–360. [PubMed][CrossRef]
38. Langermann S, Mollby R, Burlein JE, Palaszynski SR, Auguste CG, DeFusco A, Strouse R, Schenerman MA, Hultgren SJ, Pinkner JS, Winberg J, Guldevall L, Soderhall M, Ishikawa K, Normark S, Koenig S. 2000. Vaccination with FimH adhesin protects cynomolgus monkeys from colonization and infection by uropathogenic Escherichia coli. J Infect Dis 181:774–778. [PubMed][CrossRef]
39. Langermann S, Palaszynski S, Barnhart M, Auguste G, Pinkner JS, Burlein J, Barren P, Koenig S, Leath S, Jones CH, Hultgren SJ. 1997. Prevention of mucosal Escherichia coli infection by FimH-adhesin-based systemic vaccination. Science 276:607–611. [PubMed][CrossRef]
40. Roberts JA, Kaack MB, Baskin G, Chapman MR, Hunstad DA, Pinkner JS, Hultgren SJ. 2004. Antibody responses and protection from pyelonephritis following vaccination with purified Escherichia coli PapDG protein. J Urol 171:1682–1685. [PubMed][CrossRef]
41. Tseng CC, Huang JJ, Wang MC, Wu AB, Ko WC, Chen WC, Wu JJ. 2007. PapG II adhesin in the establishment and persistence of Escherichia coli infection in mouse kidneys. Kidney Int 71:764–770. [PubMed][CrossRef]
42. Hannan TJ, Mysorekar IU, Hung CS, Isaacson-Schmid ML, Hultgren SJ. 2010. Early severe inflammatory responses to uropathogenic E. coli predispose to chronic and recurrent urinary tract infection. PLoS Pathog 6:e1001042. [PubMed][CrossRef]
43. Anand M, Wang C, French J, Isaacson-Schmid M, Wall LL, Mysorekar IU. 2012. Estrogen affects the glycosaminoglycan layer of the murine bladder. Female Pelvic Med Reconstr Surg 18:148–152. [PubMed][CrossRef]
44. Thumbikat P, Waltenbaugh C, Schaeffer AJ, Klumpp DJ. 2006. Antigen-specific responses accelerate bacterial clearance in the bladder. J Immunol 176:3080–3086. [PubMed][CrossRef]
45. Hannan TJ, Roberts PL, Riehl TE, van der Post S, Binkley JM, Schwartz DJ, Miyoshi H, Mack M, Schwendener RA, Hooton TM, Stappenbeck TS, Hansson GC, Stenson WF, Colonna M, Stapleton AE, Hultgren SJ. 2014. Inhibition of Cyclooxygenase-2 Prevents Chronic and Recurrent Cystitis. EBioMedicine 1:46–57. [PubMed][CrossRef]
46. Kuehn MJ, Ogg DJ, Kihlberg J, Slonim LN, Flemmer K, Bergfors T, Hultgren SJ. 1993. Structural basis of pilus subunit recognition by the PapD chaperone. Science 262:1234–1241. [PubMed][CrossRef]
47. Sauer FG, Futterer K, Pinkner JS, Dodson KW, Hultgren SJ, Waksman G. 1999. Structural basis of chaperone function and pilus biogenesis. Science 285:1058–1061. [PubMed][CrossRef]
48. Sauer FG, Pinkner JS, Waksman G, Hultgren SJ. 2002. Chaperone priming of pilus subunits facilitates a topological transition that drives fiber formation. Cell 111:543–551. [PubMed][CrossRef]
49. Remaut H, Tang C, Henderson NS, Pinkner JS, Wang T, Hultgren SJ, Thanassi DG, Waksman G, Li H. 2008. Fiber formation across the bacterial outer membrane by the chaperone/usher pathway. Cell 133:640–652. [PubMed][CrossRef]
50. Phan G, Remaut H, Wang T, Allen WJ, Pirker KF, Lebedev A, Henderson NS, Geibel S, Volkan E, Yan J, Kunze MB, Pinkner JS, Ford B, Kay CW, Li H, Hultgren SJ, Thanassi DG, Waksman G. 2011. Crystal structure of the FimD usher bound to its cognate FimC-FimH substrate. Nature 474:49–53. [PubMed][CrossRef]
51. Waksman G, Hultgren SJ. 2009. Structural biology of the chaperone-usher pathway of pilus biogenesis. Nat Rev Microbiol 7:765–774. [PubMed][CrossRef]
52. Kuehn MJ, Heuser J, Normark S, Hultgren SJ. 1992. P pili in uropathogenic E. coli are composite fibres with distinct fibrillar adhesive tips. Nature 356:252–255. [PubMed][CrossRef]
53. Brzuszkiewicz E, Bruggemann H, Liesegang H, Emmerth M, Olschlager T, Nagy G, Albermann K, Wagner C, Buchrieser C, Emody L, Gottschalk G, Hacker J, Dobrindt U. 2006. How to become a uropathogen: comparative genomic analysis of extraintestinal pathogenic Escherichia coli strains. Proc Natl Acad Sci U S A 103:12879–12884. [PubMed][CrossRef]
54. Chen SL, Hung CS, Xu J, Reigstad CS, Magrini V, Sabo A, Blasiar D, Bieri T, Meyer RR, Ozersky P, Armstrong JR, Fulton RS, Latreille JP, Spieth J, Hooton TM, Mardis ER, Hultgren SJ, Gordon JI. 2006. Identification of genes subject to positive selection in uropathogenic strains of Escherichia coli: a comparative genomics approach. Proc Natl Acad Sci U S A 103:5977–5982. [PubMed][CrossRef]
55. Welch RA, Burland V, Plunkett G, 3rd, Redford P, Roesch P, Rasko D, Buckles EL, Liou SR, Boutin A, Hackett J, Stroud D, Mayhew GF, Rose DJ, Zhou S, Schwartz DC, Perna NT, Mobley HL, Donnenberg MS, Blattner FR. 2002. Extensive mosaic structure revealed by the complete genome sequence of uropathogenic Escherichia coli. Proc Natl Acad Sci U S A 99:17020–17024. [PubMed][CrossRef]
56. Hung CS, Bouckaert J, Hung D, Pinkner J, Widberg C, DeFusco A, Auguste CG, Strouse R, Langermann S, Waksman G, Hultgren SJ. 2002. Structural basis of tropism of Escherichia coli to the bladder during urinary tract infection. Molec Microbiol 44:903–915. [PubMed][CrossRef]
57. Choudhury D, Thompson A, Stojanoff V, Langermann S, Pinkner J, Hultgren SJ, Knight SD. 1999. X-ray structure of the FimC-FimH chaperone-adhesin complex from uropathogenic Escherichia coli. Science 285:1061–1066. [PubMed][CrossRef]
58. Zhou G, Mo W-J, Sebbel P, Min G, Neubert TA, Glockshuber R, Wu X-R, Sun T-T, Kong X-P. 2001. Uroplakin Ia is the urothelial receptor for uropathogenic Escherichia coli: evidence from in vitro FimH binding. Journal of Cell Science 114:4095–4103. [PubMed]
59. Eto DS, Jones TA, Sundsbak JL, Mulvey MA. 2007. Integrin-mediated host cell invasion by type 1-piliated uropathogenic Escherichia coli. PLoS Pathog 3:e100. [PubMed][CrossRef]
60. Mossman KL, Mian MF, Lauzon NM, Gyles CL, Lichty B, Mackenzie R, Gill N, Ashkar AA. 2008. Cutting edge: FimH adhesin of type 1 fimbriae is a novel TLR4 ligand. J Immunol 181:6702–6706. [PubMed][CrossRef]
61. Lund B, Lindberg F, Marklund BI, Normark S. 1987. The PapG protein is the alpha-D-galactopyranosyl-(1–4)-beta-D-galactopyranose-binding adhesin of uropathogenic Escherichia coli. Proc Natl Acad Sci U S A 84:5898–5902. [PubMed][CrossRef]
62. Lichodziejewska M, Topley N, Steadman R, Mackenzie RK, Jones KV, Williams JD. 1989. Variable expression of P fimbriae in Escherichia coli urinary tract infection. Lancet 1:1414–1418. [CrossRef]
63. Pere A, Nowicki B, Saxen H, Siitonen A, Korhonen TK. 1987. Expression of P, type-1, and type-1C fimbriae of Escherichia coli in the urine of patients with acute urinary tract infection. J Infect Dis 156:567–574. [PubMed][CrossRef]
64. Kisielius PV, Schwan WR, Amundsen SK, Duncan JL, Schaeffer AJ. 1989. In vivo expression and variation of Escherichia coli type 1 and P pili in the urine of adults with acute urinary tract infections. Infect Immun 57:1656–1662. [PubMed]
65. Hultgren SJ, Porter TN, Schaeffer AJ, Duncan JL. 1985. Role of type 1 pili and effects of phase variation on lower urinary tract infections produced by Escherichia coli. Infect Immun 50:370–377. [PubMed]
66. Greene SE, Hibbing ME, Janetka J, Chen SL, Hultgren SJ. 2015. Human urine decreases function and expression of type 1 pili in uropathogenic Escherichia coli. MBio 6:e00820. [PubMed][CrossRef]
67. Hagberg L, Hull R, Hull S, Falkow S, Freter R, Svanborg Eden C. 1983. Contribution of adhesion to bacterial persistence in the mouse urinary tract. Infect Immun 40:265–272. [PubMed]
68. Abraham JM, Freitag CS, Clements JR, Eisenstein BI. 1985. An invertible element of DNA controls phase variation of type 1 fimbriae of Escherichia coli. Proc Natl Acad Sci U S A 82:5724–5727. [PubMed][CrossRef]
69. Alkan ML, Wong L, Silverblatt FJ. 1986. Change in degree of type 1 piliation of Escherichia coli during experimental peritonitis in the mouse. Infect Immun 54:549–554. [PubMed]
70. Bahrani-Mougeot FK, Buckles EL, Lockatell CV, Hebel JR, Johnson DE, Tang CM, Donnenberg MS. 2002. Type 1 fimbriae and extracellular polysaccharides are preeminent uropathogenic Escherichia coli virulence determinants in the murine urinary tract. Mol Microbiol 45:1079–1093. [PubMed][CrossRef]
71. Wright KJ, Seed PC, Hultgren SJ. 2007. Development of intracellular bacterial communities of uropathogenic Escherichia coli depends on type 1 pili. Cell Microbiol 9:2230–2241. [PubMed][CrossRef]
72. Martinez JJ, Mulvey MA, Schilling JD, Pinkner JS, Hultgren SJ. 2000. Type 1 pilus-mediated bacterial invasion of bladder epithelial cells. EMBO J 19:2803–2812. [PubMed][CrossRef]
73. Chen SL, Hung CS, Pinkner JS, Walker JN, Cusumano CK, Li Z, Bouckaert J, Gordon JI, Hultgren SJ. 2009. Positive selection identifies an in vivo role for FimH during urinary tract infection in addition to mannose binding. Proc Natl Acad Sci U S A 106:22439–22444. [PubMed][CrossRef]
74. Schembri MA, Sokurenko EV, Klemm P. 2000. Functional flexibility of the FimH adhesin: insights from a random mutant library. Infect Immun 68:2638–2646. [PubMed][CrossRef]
75. Sokurenko EV, Chesnokova V, Dykhuizen DE, Ofek I, Wu XR, Krogfelt KA, Struve C, Schembri MA, Hasty DL. 1998. Pathogenic adaptation of Escherichia coli by natural variation of the FimH adhesin. Proc Natl Acad Sci U S A 95:8922–8926. [PubMed][CrossRef]
76. Sokurenko EV, Courtney HS, Maslow J, Siitonen A, Hasty DL. 1995. Quantitative differences in adhesiveness of type 1 fimbriated Escherichia coli due to structural differences in fimH genes. J Bacteriol 177:3680–3686. [PubMed]
77. Sokurenko EV, Courtney HS, Ohman DE, Klemm P, Hasty DL. 1994. FimH family of type 1 fimbrial adhesins: functional heterogeneity due to minor sequence variations among fimH genes. J Bacteriol 176:748–755. [PubMed]
78. Schwartz DJ, Kalas V, Pinkner JS, Chen SL, Spaulding CN, Dodson KW, Hultgren SJ. 2013. Positively selected FimH residues enhance virulence during urinary tract infection by altering FimH conformation. Proc Natl Acad Sci U S A 110:15530–15537. [PubMed][CrossRef]
79. Thumbikat P, Berry RE, Zhou G, Billips BK, Yaggie RE, Zaichuk T, Sun TT, Schaeffer AJ, Klumpp DJ. 2009. Bacteria-induced uroplakin signaling mediates bladder response to infection. PLoS Pathog 5:e1000415. [PubMed][CrossRef]
80. Wang H, Min G, Glockshuber R, Sun TT, Kong XP. 2009. Uropathogenic E. coli adhesin-induced host cell receptor conformational changes: implications in transmembrane signaling transduction. J Mol Biol 392:352–361. [PubMed][CrossRef]
81. Eto DS, Gordon HB, Dhakal BK, Jones TA, Mulvey MA. 2008. Clathrin, AP-2, and the NPXY-binding subset of alternate endocytic adaptors facilitate FimH-mediated bacterial invasion of host cells. Cell Microbiol 10:2553–2567. [PubMed][CrossRef]
82. Duncan MJ, Li G, Shin JS, Carson JL, Abraham SN. 2004. Bacterial penetration of bladder epithelium through lipid rafts. J Biol Chem 279:18944–18951. [PubMed][CrossRef]
83. Dhakal BK, Mulvey MA. 2009. Uropathogenic Escherichia coli invades host cells via an HDAC6-modulated microtubule-dependent pathway. J Biol Chem 284:446–454. [PubMed][CrossRef]
84. Martinez JJ, Hultgren SJ. 2002. Requirement of Rho-family GTPases in the invasion of Type 1-piliated uropathogenic Escherichia coli. Cell Microbiol 4:19–28. [CrossRef]
85. Song J, Bishop BL, Li G, Duncan MJ, Abraham SN. 2007. TLR4-initiated and cAMP-mediated abrogation of bacterial invasion of the bladder. Cell Host Microbe 1:287–298. [PubMed][CrossRef]
86. Doye A, Mettouchi A, Bossis G, Clement R, Buisson-Touati C, Flatau G, Gagnoux L, Piechaczyk M, Boquet P, Lemichez E. 2002. CNF1 exploits the ubiquitin-proteasome machinery to restrict Rho GTPase activation for bacterial host cell invasion. Cell 111:553–564. [PubMed][CrossRef]
87. Rippere-Lampe KE, O’Brien AD, Conran R, Lockman HA. 2001. Mutation of the gene encoding cytotoxic necrotizing factor type 1 (cnf(1)) attenuates the virulence of uropathogenic Escherichia coli. Infect Immun 69:3954–3964. [PubMed][CrossRef]
88. Johnson DE, Drachenberg C, Lockatell CV, Island MD, Warren JW, Donnenberg MS. 2000. The role of cytotoxic necrotizing factor-1 in colonization and tissue injury in a murine model of urinary tract infection. FEMS Immunol Med Microbiol 28:37–41. [PubMed][CrossRef]
89. Kallenius G, Mollby R, Svenson SB, Helin I, Hultberg H, Cedergren B, Winberg J. 1981. Occurrence of P-fimbriated Escherichia coli in urinary tract infections. Lancet 2:1369–1372. [PubMed][CrossRef]
90. Winberg J. 1984. P-fimbriae, bacterial adhesion, and pyelonephritis. Arch Dis Child 59:180–184. [PubMed][CrossRef]
91. Norinder BS, Koves B, Yadav M, Brauner A, Svanborg C. 2011. Do Escherichia coli strains causing acute cystitis have a distinct virulence repertoire? Microb Pathog doi:S0882-4010(11)00157-4 [pii] 10.1016/j.micpath.2011.08.005. [PubMed]
92. Dodson KW, Pinkner JS, Rose T, Magnusson G, Hultgren SJ, Waksman G. 2001. Structural basis of the interaction of the pyelonephritic E. coli adhesin to its human kidney receptor. Cell 105:733–743. [PubMed][CrossRef]
93. Kallenius G, Svenson S, Mollby R, Cedergren B, Hultberg H, Winberg J. 1981. Structure of carbohydrate part of receptor on human uroepithelial cells for pyelonephritogenic Escherichia coli. Lancet 2:604–606. [PubMed][CrossRef]
94. Leffler H, Lomberg H, Gotschlich E, Hagberg L, Jodal U, Korhonen T, Samuelsson BE, Schoolnik G, Svanborg-Eden C. 1982. Chemical and clinical studies on the interaction of Escherichia coli with host glycolipid receptors in urinary tract infection. Scand J Infect Dis Suppl 33:46–51. [PubMed]
95. Stapleton AE, Stroud MR, Hakomori SI, Stamm WE. 1998. The globoseries glycosphingolipid sialosyl galactosyl globoside is found in urinary tract tissues and is a preferred binding receptor In vitro for uropathogenic Escherichia coli expressing pap-encoded adhesins. Infect Immun 66:3856–3861. [PubMed]
96. de Ree JM, van den Bosch JF. 1987. Serological response to the P fimbriae of uropathogenic Escherichia coli in pyelonephritis. Infect Immun 55:2204–2207. [PubMed]
97. Kantele A, Papunen R, Virtanen E, Mottonen T, Rasanen L, Ala-Kaila K, Makela PH, Arvilommi H. 1994. Antibody-secreting cells in acute urinary tract infection as indicators of local immune response. J Infect Dis 169:1023–1028. [PubMed][CrossRef]
98. Lomberg H, Cedergren B, Leffler H, Nilsson B, Carlstrom AS, Svanborg-Eden C. 1986. Influence of blood group on the availability of receptors for attachment of uropathogenic Escherichia coli. Infect Immun 51:919–926. [PubMed]
99. Stapleton A, Hooton TM, Fennell C, Roberts PL, Stamm WE. 1995. Effect of secretor status on vaginal and rectal colonization with fimbriated Escherichia coli in women with and without recurrent urinary tract infection. J Infect Dis 171:717–720. [PubMed][CrossRef]
100. Sheinfeld J, Schaeffer AJ, Cordon-Cardo C, Rogatko A, Fair WR. 1989. Association of the Lewis blood-group phenotype with recurrent urinary tract infections in women. N Engl J Med 320:773–777. [PubMed][CrossRef]
101. Kinane DF, Blackwell CC, Brettle RP, Weir DM, Winstanley FP, Elton RA. 1982. ABO blood group, secretor state, and susceptibility to recurrent urinary tract infection in women. Br Med J (Clin Res Ed) 285:7–9. [PubMed][CrossRef]
102. Roberts JA, Marklund BI, Ilver D, Haslam D, Kaack MB, Baskin G, Louis M, Mollby R, Winberg J, Normark S. 1994. The Gal(alpha 1-4)Gal-specific tip adhesin of Escherichia coli P-fimbriae is needed for pyelonephritis to occur in the normal urinary tract. Proc Natl Acad Sci USA 91:11889–11893. [PubMed][CrossRef]
103. Roberts JA, Kaack MB, Baskin G, Marklund BI, Normark S. 1997. Epitopes of the P-fimbrial adhesin of E. coli cause different urinary tract infections. J Urol 158:1610–1613. [PubMed][CrossRef]
104. Johnson JR, Russo TA, Brown JJ, Stapleton A. 1998. papG alleles of Escherichia coli strains causing first-episode or recurrent acute cystitis in adult women. J Infect Dis 177:97–101. [PubMed][CrossRef]
105. Winberg J, Mollby R, Bergstrom J, Karlsson KA, Leonardsson I, Milh MA, Teneberg S, Haslam D, Marklund BI, Normark S. 1995. The PapG-adhesin at the tip of P-fimbriae provides Escherichia coli with a competitive edge in experimental bladder infections of cynomolgus monkeys. J Exp Med 182:1695–1702. [PubMed][CrossRef]
106. Mobley HL, Jarvis KG, Elwood JP, Whittle DI, Lockatell CV, Russell RG, Johnson DE, Donnenberg MS, Warren JW. 1993. Isogenic P-fimbrial deletion mutants of pyelonephritogenic Escherichia coli: the role of alpha Gal(1-4) beta Gal binding in virulence of a wild-type strain. Mol Microbiol 10:143–155. [PubMed][CrossRef]
107. Xu H, Storch T, Yu M, Elliott SP, Haslam DB. 1999. Characterization of the human Forssman synthetase gene. An evolving association between glycolipid synthesis and host-microbial interactions. J Biol Chem 274:29390–29398. [PubMed][CrossRef]
108. Murawski IJ, Maina RW, Malo D, Guay-Woodford LM, Gros P, Fujiwara M, Morgan K, Gupta IR. 2010. The C3H/HeJ inbred mouse is a model of vesico-ureteric reflux with a susceptibility locus on chromosome 12. Kidney Int 78:269–278. [PubMed][CrossRef]
109. Melican K, Sandoval RM, Kader A, Josefsson L, Tanner GA, Molitoris BA, Richter-Dahlfors A. 2011. Uropathogenic Escherichia coli P and Type 1 fimbriae act in synergy in a living host to facilitate renal colonization leading to nephron obstruction. PLoS Pathog 7:e1001298. [PubMed][CrossRef]
110. Korhonen TK, Parkkinen J, Hacker J, Finne J, Pere A, Rhen M, Holthofer H. 1986. Binding of Escherichia coli S fimbriae to human kidney epithelium. Infect Immun 54:322–327. [PubMed]
111. Virkola R, Westerlund B, Holthofer H, Parkkinen J, Kekomaki M, Korhonen TK. 1988. Binding characteristics of Escherichia coli adhesins in human urinary bladder. Infect Immun 56:2615–2622. [PubMed]
112. Backhed F, Alsen B, Roche N, Angstrom J, von Euler A, Breimer ME, Westerlund-Wikstrom B, Teneberg S, Richter-Dahlfors A. 2002. Identification of target tissue glycosphingolipid receptors for uropathogenic, F1C-fimbriated Escherichia coli and its role in mucosal inflammation. J Biol Chem 277:18198–18205. [PubMed][CrossRef]
113. Selvarangan R, Goluszko P, Singhal J, Carnoy C, Moseley S, Hudson B, Nowicki S, Nowicki B. 2004. Interaction of Dr adhesin with collagen type IV is a critical step in Escherichia coli renal persistence. Infect Immun 72:4827–4835. [PubMed][CrossRef]
114. Marre R, Hacker J, Henkel W, Goebel W. 1986. Contribution of cloned virulence factors from uropathogenic Escherichia coli strains to nephropathogenicity in an experimental rat pyelonephritis model. Infect Immun 54:761–767. [PubMed]
115. Blanco M, Blanco JE, Alonso MP, Mora A, Balsalobre C, Munoa F, Juarez A, Blanco J. 1997. Detection of pap, sfa and afa adhesin-encoding operons in uropathogenic Escherichia coli strains: relationship with expression of adhesins and production of toxins. Res Microbiol 148:745–755. [CrossRef]
116. Qin X, Hu F, Wu S, Ye X, Zhu D, Zhang Y, Wang M. 2013. Comparison of adhesin genes and antimicrobial susceptibilities between uropathogenic and intestinal commensal Escherichia coli strains. PLoS One 8:e61169. [PubMed][CrossRef]
117. Spurbeck RR, Stapleton AE, Johnson JR, Walk ST, Hooton TM, Mobley HL. 2011. Fimbrial profiles predict virulence of uropathogenic Escherichia coli strains: contribution of ygi and yad fimbriae. Infect Immun 79:4753–4763. [PubMed][CrossRef]
118. Vigil PD, Alteri CJ, Mobley HL. 2011. Identification of in vivo-induced antigens including an RTX family exoprotein required for uropathogenic Escherichia coli virulence. Infect Immun 79:2335–2344. [PubMed][CrossRef]
119. Vigil PD, Stapleton AE, Johnson JR, Hooton TM, Hodges AP, He Y, Mobley HL. 2011. Presence of putative repeat-in-toxin gene tosA in Escherichia coli predicts successful colonization of the urinary tract. MBio 2:e00066-00011. [PubMed][CrossRef]
120. Engstrom MD, Alteri CJ, Mobley HL. 2014. A conserved PapB family member, TosR, regulates expression of the uropathogenic Escherichia coli RTX nonfimbrial adhesin TosA while conserved LuxR family members TosE and TosF suppress motility. Infect Immun 82:3644–3656. [PubMed][CrossRef]
121. Vigil PD, Wiles TJ, Engstrom MD, Prasov L, Mulvey MA, Mobley HL. 2012. The repeat-in-toxin family member TosA mediates adherence of uropathogenic Escherichia coli and survival during bacteremia. Infect Immun 80:493–505. [PubMed][CrossRef]
122. Nesta B, Spraggon G, Alteri C, Moriel DG, Rosini R, Veggi D, Smith S, Bertoldi I, Pastorello I, Ferlenghi I, Fontana MR, Frankel G, Mobley HL, Rappuoli R, Pizza M, Serino L, Soriani M. 2012. FdeC, a novel broadly conserved Escherichia coli adhesin eliciting protection against urinary tract infections. MBio 3. [PubMed][CrossRef]
123. Johnson JR, Jelacic S, Schoening LM, Clabots C, Shaikh N, Mobley HL, Tarr PI. 2005. The IrgA homologue adhesin Iha is an Escherichia coli virulence factor in murine urinary tract infection. Infect Immun 73:965–971. [PubMed][CrossRef]
124. Bishop BL, Duncan MJ, Song J, Li G, Zaas D, Abraham SN. 2007. Cyclic AMP-regulated exocytosis of Escherichia coli from infected bladder epithelial cells. Nat Med 13:625–630. [PubMed][CrossRef]
125. Song J, Bishop BL, Li G, Grady R, Stapleton A, Abraham SN. 2009. TLR4-mediated expulsion of bacteria from infected bladder epithelial cells. Proc Natl Acad Sci U S A 106:14966–14971. [PubMed][CrossRef]
126. Mulvey MA, Schilling JD, Hultgren SJ. 2001. Establishment of a persistent Escherichia coli reservoir during the acute phase of a bladder infection. Infect Immun 69:4572–4579. [PubMed][CrossRef]
127. Wei Y, Li K, Wang N, Cai GD, Zhang T, Lin Y, Gui BS, Liu EQ, Li ZF, Zhou W. 2015. Activation of endogenous anti-inflammatory mediator cyclic AMP attenuates acute pyelonephritis in mice induced by uropathogenic Escherichia coli. Am J Pathol 185:472–484. [PubMed][CrossRef]
128. Schilling JD, Mulvey MA, Vincent CD, Lorenz RG, Hultgren SJ. 2001. Bacterial invasion augments epithelial cytokine responses to Escherichia coli through a lipopolysaccharide-dependent mechanism. J Immunol 166:1148–1155. [PubMed][CrossRef]
129. Wang C, Mendonsa GR, Symington JW, Zhang Q, Cadwell K, Virgin HW, Mysorekar IU. 2012. Atg16L1 deficiency confers protection from uropathogenic Escherichia coli infection in vivo. Proc Natl Acad Sci U S A 109:11008–11013. [PubMed][CrossRef]
130. Li B, Smith P, Horvath DJ, Jr., Romesberg FE, Justice SS. 2010. SOS regulatory elements are essential for UPEC pathogenesis. Microbes Infect 12:662–668. [PubMed][CrossRef]
131. Blango MG, Mulvey MA. 2010. Persistence of uropathogenic Escherichia coli in the face of multiple antibiotics. Antimicrob Agents Chemother 54:1855–1863. [PubMed][CrossRef]
132. Wieser A, Guggenberger C, Pritsch M, Heesemann J, Schubert S. 2011. A novel ex vivo set-up for dynamic long-term characterization of processes on mucosal interfaces by confocal imaging and simultaneous cytokine measurements. Cell Microbiol 13:742–751. [PubMed][CrossRef]
133. Eto DS, Sundsbak JL, Mulvey MA. 2006. Actin-gated intracellular growth and resurgence of uropathogenic Escherichia coli. Cell Microbiol 8:704–717. [PubMed][CrossRef]
134. Berry RE, Klumpp DJ, Schaeffer AJ. 2009. Urothelial cultures support intracellular bacterial community formation by uropathogenic Escherichia coli. Infect Immun 77:2762–2772. [PubMed][CrossRef]
135. Reigstad CS, Hultgren SJ, Gordon JI. 2007. Functional genomic studies of uropathogenic Escherichia coli and host urothelial cells when intracellular bacterial communities are assembled. J Biol Chem 282:21259–21267. [PubMed][CrossRef]
136. Hannan TJ, Mysorekar IU, Chen SL, Walker JN, Jones JM, Pinkner JS, Hultgren SJ, Seed PC. 2008. LeuX tRNA-dependent and -independent mechanisms of Escherichia coli pathogenesis in acute cystitis. Mol Microbiol 67:116–128. [PubMed]
137. Justice SS, Lauer SR, Hultgren SJ, Hunstad DA. 2006. Maturation of intracellular Escherichia coli communities requires SurA. Infect Immun 74:4793–4800. [PubMed][CrossRef]
138. Cusumano CK, Hung CS, Chen SL, Hultgren SJ. 2010. Virulence plasmid harbored by uropathogenic Escherichia coli functions in acute stages of pathogenesis. Infect Immun 78:1457–1467. [PubMed][CrossRef]
139. Rosen DA, Pinkner JS, Walker JN, Elam JS, Jones JM, Hultgren SJ. 2008. Molecular variations in Klebsiella pneumoniae and Escherichia coli FimH affect function and pathogenesis in the urinary tract. Infect Immun 76:3346–3356. [PubMed][CrossRef]
140. Cegelski L, Marshall GR, Eldridge GR, Hultgren SJ. 2008. The biology and future prospects of antivirulence therapies. Natl Rev Microbiol 6:17–27. [PubMed][CrossRef]
141. Monack DM, Mueller A, Falkow S. 2004. Persistent bacterial infections: the interface of the pathogen and the host immune system. Natl Rev Microbiol 2:747–765. [PubMed][CrossRef]
142. Anderson GG, Goller CC, Justice S, Hultgren SJ, Seed PC. 2010. Polysaccharide capsule and sialic acid-mediated regulation promote biofilm-like intracellular bacterial communities during cystitis. Infect Immun 78:963–975. [PubMed][CrossRef]
143. Buckles EL, Wang X, Lane MC, Lockatell CV, Johnson DE, Rasko DA, Mobley HL, Donnenberg MS. 2009. Role of the K2 capsule in Escherichia coli urinary tract infection and serum resistance. J Infect Dis 199:1689–1697. [PubMed][CrossRef]
144. Cegelski L, Pinkner JS, Hammer ND, Cusumano CK, Hung CS, Chorell E, Aberg V, Walker JN, Seed PC, Almqvist F, Chapman MR, Hultgren SJ. 2009. Small-molecule inhibitors target Escherichia coli amyloid biogenesis and biofilm formation. Natl Chem Biol 5:913–919. [PubMed][CrossRef]
145. Allsopp LP, Beloin C, Ulett GC, Valle J, Totsika M, Sherlock O, Ghigo JM, Schembri MA. 2011. Molecular characterization of UpaB and UpaC - two new autotransporter proteins of uropathogenic Escherichia coli CFT073. Infect Immun doi:IAI.05322-11 [pii] 10.1128/IAI.05322-11. [PubMed]
146. Allsopp LP, Totsika M, Tree JJ, Ulett GC, Mabbett AN, Wells TJ, Kobe B, Beatson SA, Schembri MA. 2010. UpaH is a newly identified autotransporter protein that contributes to biofilm formation and bladder colonization by uropathogenic Escherichia coli CFT073. Infect Immun 78:1659–1669. [PubMed][CrossRef]
147. Ulett GC, Valle J, Beloin C, Sherlock O, Ghigo JM, Schembri MA. 2007. Functional analysis of antigen 43 in uropathogenic Escherichia coli reveals a role in long-term persistence in the urinary tract. Infect Immun 75:3233–3244. [PubMed][CrossRef]
148. Valle J, Mabbett AN, Ulett GC, Toledo-Arana A, Wecker K, Totsika M, Schembri MA, Ghigo JM, Beloin C. 2008. UpaG, a new member of the trimeric autotransporter family of adhesins in uropathogenic Escherichia coli. J Bacteriol 190:4147–4161. [PubMed][CrossRef]
149. Garofalo CK, Hooton TM, Martin SM, Stamm WE, Palermo JJ, Gordon JI, Hultgren SJ. 2007. Escherichia coli from urine of female patients with urinary tract infections is competent for intracellular bacterial community formation. Infect Immun 75:52–60. [PubMed][CrossRef]
150. Cusumano CK, Pinkner JS, Han Z, Greene SE, Ford BA, Crowley JR, Henderson JP, Janetka JW, Hultgren SJ. 2011. Treatment and prevention of urinary tract infection with orally active FimH inhibitors. Sci Transl Med 3:109ra115. [PubMed][CrossRef]
151. Mysorekar IU, Hultgren SJ. 2006. Mechanisms of uropathogenic Escherichia coli persistence and eradication from the urinary tract. Proc Natl Acad Sci U S A 103:14170–14175. [PubMed][CrossRef]
152. Rosen DA, Pinkner JS, Jones JM, Walker JN, Clegg S, Hultgren SJ. 2008. Utilization of an intracellular bacterial community pathway in Klebsiella pneumoniae urinary tract infection and the effects of FimK on type 1 pilus expression. Infect Immun 76:3337–3345. [PubMed][CrossRef]
153. Wright KJ, Seed PC, Hultgren SJ. 2005. Uropathogenic Escherichia coli Flagella Aid in Efficient Urinary Tract Colonization. Infect Immun 73:7657–7668. [PubMed][CrossRef]
154. Justice SS, Hunstad DA, Seed PC, Hultgren SJ. 2006. Filamentation by Escherichia coli subverts innate defenses during urinary tract infection. Proc Natl Acad Sci USA 103:19884–19889. [PubMed][CrossRef]
155. Alteri CJ, Smith SN, Mobley HL. 2009. Fitness of Escherichia coli during urinary tract infection requires gluconeogenesis and the TCA cycle. PLoS Pathog 5:e1000448. [PubMed][CrossRef]
156. Hadjifrangiskou M, Kostakioti M, Chen SL, Henderson JP, Greene SE, Hultgren SJ. 2011. A central metabolic circuit controlled by QseC in pathogenic Escherichia coli. Mol Microbiol 80:1516–1529. [PubMed][CrossRef]
157. Kostakioti M, Hadjifrangiskou M, Pinkner JS, Hultgren SJ. 2009. QseC-mediated dephosphorylation of QseB is required for expression of genes associated with virulence in uropathogenic Escherichia coli. Mol Microbiol 73:1020–1031. [PubMed][CrossRef]
158. Alteri CJ, Himpsl SD, Mobley HL. 2015. Preferential use of central metabolism in vivo reveals a nutritional basis for polymicrobial infection. PLoS Pathog 11:e1004601. [PubMed][CrossRef]
159. Hryckowian AJ, Welch RA. 2013. RpoS contributes to phagocyte oxidase-mediated stress resistance during urinary tract infection by Escherichia coli CFT073. MBio 4:e00023-00013. [PubMed][CrossRef]
160. Clarke MB, Hughes DT, Zhu C, Boedeker EC, Sperandio V. 2006. The QseC sensor kinase: a bacterial adrenergic receptor. Proc Natl Acad Sci U S A 103:10420–10425. [PubMed][CrossRef]
161. Rasko DA, Moreira CG, Li de R, Reading NC, Ritchie JM, Waldor MK, Williams N, Taussig R, Wei S, Roth M, Hughes DT, Huntley JF, Fina MW, Falck JR, Sperandio V. 2008. Targeting QseC signaling and virulence for antibiotic development. Science 321:1078–1080. [PubMed][CrossRef]
162. Sperandio V, Torres AG, Kaper JB. 2002. Quorum sensing Escherichia coli regulators B and C (QseBC): a novel two-component regulatory system involved in the regulation of flagella and motility by quorum sensing in E. coli. Mol Microbiol 43:809–821. [PubMed][CrossRef]
163. Kostakioti M, Hadjifrangiskou M, Cusumano CK, Hannan TJ, Janetka JW, Hultgren SJ. 2012. Distinguishing the contribution of type 1 pili from that of other QseB-misregulated factors when QseC is absent during urinary tract infection. Infect Immun 80:2826–2834. [PubMed][CrossRef]
164. Guckes KR, Kostakioti M, Breland EJ, Gu AP, Shaffer CL, Martinez CR, 3rd, Hultgren SJ, Hadjifrangiskou M. 2013. Strong cross-system interactions drive the activation of the QseB response regulator in the absence of its cognate sensor. Proc Natl Acad Sci U S A 110:16592–16597. [PubMed][CrossRef]
165. Hung DL, Raivio TL, Jones CH, Silhavy TJ, Hultgren SJ. 2001. Cpx signaling pathway monitors biogenesis and affects assembly and expression of P pili. EMBO J 20:1508–1518. [PubMed][CrossRef]
166. Hernday AD, Braaten BA, Broitman-Maduro G, Engelberts P, Low DA. 2004. Regulation of the pap epigenetic switch by CpxAR: phosphorylated CpxR inhibits transition to the phase ON state by competition with Lrp. Mol Cell 16:537–547. [PubMed][CrossRef]
167. Debnath I, Norton JP, Barber AE, Ott EM, Dhakal BK, Kulesus RR, Mulvey MA. 2013. The Cpx stress response system potentiates the fitness and virulence of uropathogenic Escherichia coli. Infect Immun 81:1450–1459. [PubMed][CrossRef]
168. Alteri CJ, Lindner JR, Reiss DJ, Smith SN, Mobley HL. 2011. The broadly conserved regulator PhoP links pathogen virulence and membrane potential in Escherichia coli. Mol Microbiol 82:145–163. [PubMed][CrossRef]
169. Palaniyandi S, Mitra A, Herren CD, Lockatell CV, Johnson DE, Zhu X, Mukhopadhyay S. 2012. BarA-UvrY two-component system regulates virulence of uropathogenic E. coli CFT073. PLoS One 7:e31348. [PubMed][CrossRef]
170. Cai W, Wannemuehler Y, Dell’anna G, Nicholson B, Barbieri NL, Kariyawasam S, Feng Y, Logue CM, Nolan LK, Li G. 2013. A novel two-component signaling system facilitates uropathogenic Escherichia coli’s ability to exploit abundant host metabolites. PLoS Pathog 9:e1003428. [PubMed][CrossRef]
171. Crepin S, Houle S, Charbonneau ME, Mourez M, Harel J, Dozois CM. 2012. Decreased expression of type 1 fimbriae by a pst mutant of uropathogenic Escherichia coli reduces urinary tract infection. Infect Immun 80:2802–2815. [PubMed][CrossRef]
172. Skaar EP. 2010. The battle for iron between bacterial pathogens and their vertebrate hosts. PLoS Pathog 6:e1000949. [PubMed][CrossRef]
173. Williams PH, Carbonetti NH. 1986. Iron, siderophores, and the pursuit of virulence: independence of the aerobactin and enterochelin iron uptake systems in Escherichia coli. Infect Immun 51:942–947. [PubMed]
174. Valdebenito M, Bister B, Reissbrodt R, Hantke K, Winkelmann G. 2005. The detection of salmochelin and yersiniabactin in uropathogenic Escherichia coli strains by a novel hydrolysis-fluorescence-detection (HFD) method. Int J Med Microbiol 295:99–107. [PubMed][CrossRef]
175. Bachman MA, Oyler JE, Burns SH, Caza M, Lepine F, Dozois CM, Weiser JN. 2011. Klebsiella pneumoniae yersiniabactin promotes respiratory tract infection through evasion of lipocalin 2. Infect Immun 79:3309–3316. [PubMed][CrossRef]
176. Henderson JP, Crowley JR, Pinkner JS, Walker JN, Tsukayama P, Stamm WE, Hooton TM, Hultgren SJ. 2009. Quantitative metabolomics reveals an epigenetic blueprint for iron acquisition in uropathogenic Escherichia coli. PLoS Pathog 5:e1000305. [PubMed][CrossRef]
177. Raffatellu M, George MD, Akiyama Y, Hornsby MJ, Nuccio SP, Paixao TA, Butler BP, Chu H, Santos RL, Berger T, Mak TW, Tsolis RM, Bevins CL, Solnick JV, Dandekar S, Baumler AJ. 2009. Lipocalin-2 resistance confers an advantage to Salmonella enterica serotype Typhimurium for growth and survival in the inflamed intestine. Cell Host Microbe 5:476–486. [PubMed][CrossRef]
178. Porcheron G, Habib R, Houle S, Caza M, Lepine F, Daigle F, Masse E, Dozois CM. 2014. The small RNA RyhB contributes to siderophore production and virulence of uropathogenic Escherichia coli. Infect Immun 82:5056–5068. [PubMed][CrossRef]
179. Feldmann F, Sorsa LJ, Hildinger K, Schubert S. 2007. The salmochelin siderophore receptor IroN contributes to invasion of urothelial cells by extraintestinal pathogenic Escherichia coli in vitro. Infect Immun 75:3183–3187. [PubMed][CrossRef]
180. Russo TA, McFadden CD, Carlino-MacDonald UB, Beanan JM, Olson R, Wilding GE. 2003. The Siderophore receptor IroN of extraintestinal pathogenic Escherichia coli is a potential vaccine candidate. Infect Immun 71:7164–7169. [PubMed][CrossRef]
181. Chaturvedi KS, Hung CS, Crowley JR, Stapleton AE, Henderson JP. 2012. The siderophore yersiniabactin binds copper to protect pathogens during infection. Nat Chem Biol doi:nchembio.1020 [pii] 10.1038/nchembio.1020. [PubMed]
182. Watts RE, Totsika M, Challinor VL, Mabbett AN, Ulett GC, De Voss JJ, Schembri MA. 2012. Contribution of siderophore systems to growth and urinary tract colonization of asymptomatic bacteriuria Escherichia coli. Infect Immun 80:333–344. [PubMed][CrossRef]
183. Garcia EC, Brumbaugh AR, Mobley HL. 2011. Redundancy and specificity of Escherichia coli iron acquisition systems during urinary tract infection. Infect Immun 79:1225–1235. [PubMed][CrossRef]
184. Torres AG, Redford P, Welch RA, Payne SM. 2001. TonB-dependent systems of uropathogenic Escherichia coli: aerobactin and heme transport and TonB are required for virulence in the mouse. Infect Immun 69:6179–6185. [PubMed][CrossRef]
185. Blango MG, Ott EM, Erman A, Veranic P, Mulvey MA. 2014. Forced resurgence and targeting of intracellular uropathogenic Escherichia coli reservoirs. PLoS One 9:e93327. [PubMed][CrossRef]
186. Hopkins WJ, Gendron-Fitzpatrick A, Balish E, Uehling DT. 1998. Time course and host responses to Escherichia coli urinary tract infection in genetically distinct mouse strains. Infect Immun 66:2798–2802. [PubMed]
187. Schwartz DJ, Conover MS, Hannan TJ, Hultgren SJ. 2015. Uropathogenic Escherichia coli superinfection enhances the severity of mouse bladder infection. PLoS Pathog 11:e1004599. [PubMed][CrossRef]
188. Ferry SA, Holm SE, Stenlund H, Lundholm R, Monsen TJ. 2004. The natural course of uncomplicated lower urinary tract infection in women illustrated by a randomized placebo controlled study. Scand J Infect Dis 36:296–301. [PubMed][CrossRef]
189. Mabeck CE. 1972. Treatment of uncomplicated urinary tract infection in non-pregnant women. Postgrad Med J 48:69–75. [PubMed][CrossRef]
190. Bleidorn J, Gagyor I, Kochen MM, Wegscheider K, Hummers-Pradier E. 2010. Symptomatic treatment (ibuprofen) or antibiotics (ciprofloxacin) for uncomplicated urinary tract infection?--results of a randomized controlled pilot trial. BMC Med 8:30. [PubMed][CrossRef]
191. Lane MC, Alteri CJ, Smith SN, Mobley HL. 2007. Expression of flagella is coincident with uropathogenic Escherichia coli ascension to the upper urinary tract. Proc Natl Acad Sci U S A 104:16669–16674. [PubMed][CrossRef]
192. Lane MC, Lockatell V, Monterosso G, Lamphier D, Weinert J, Hebel JR, Johnson DE, Mobley HL. 2005. Role of motility in the colonization of uropathogenic Escherichia coli in the urinary tract. Infect Immun 73:7644–7656. [PubMed][CrossRef]
193. O’Hanley P, Lalonde G, Ji G. 1991. Alpha-hemolysin contributes to the pathogenicity of piliated digalactoside-binding Escherichia coli in the kidney: efficacy of an alpha-hemolysin vaccine in preventing renal injury in the BALB/c mouse model of pyelonephritis. Infect Immun 59:1153–1161. [PubMed]
194. Uhlen P, Laestadius A, Jahnukainen T, Soderblom T, Backhed F, Celsi G, Brismar H, Normark S, Aperia A, Richter-Dahlfors A. 2000. Alpha-haemolysin of uropathogenic E. coli induces Ca2+ oscillations in renal epithelial cells. Nature 405:694–697. [PubMed][CrossRef]
195. Nagamatsu K, Hannan TJ, Guest RL, Kostakioti M, Hadjifrangiskou M, Binkley J, Dodson K, Raivio TL, Hultgren SJ. 2015. Dysregulation of Escherichia coli alpha-hemolysin expression alters the course of acute and persistent urinary tract infection. Proc Natl Acad Sci U S A 112:E871–880. [PubMed][CrossRef]
196. Guyer DM, Radulovic S, Jones FE, Mobley HL. 2002. Sat, the secreted autotransporter toxin of uropathogenic Escherichia coli, is a vacuolating cytotoxin for bladder and kidney epithelial cells. Infect Immun 70:4539–4546. [PubMed][CrossRef]
197. Heimer SR, Rasko DA, Lockatell CV, Johnson DE, Mobley HL. 2004. Autotransporter genes pic and tsh are associated with Escherichia coli strains that cause acute pyelonephritis and are expressed during urinary tract infection. Infect Immun 72:593–597. [PubMed][CrossRef]
198. Hagan EC, Mobley HL. 2009. Haem acquisition is facilitated by a novel receptor Hma and required by uropathogenic Escherichia coli for kidney infection. Mol Microbiol 71:79–91. [PubMed][CrossRef]
199. Kulkarni R, Dhakal BK, Slechta ES, Kurtz Z, Mulvey MA, Thanassi DG. 2009. Roles of putative type II secretion and type IV pilus systems in the virulence of uropathogenic Escherichia coli. PLoS One 4:e4752. [PubMed][CrossRef]
200. Cirl C, Wieser A, Yadav M, Duerr S, Schubert S, Fischer H, Stappert D, Wantia N, Rodriguez N, Wagner H, Svanborg C, Miethke T. 2008. Subversion of Toll-like receptor signaling by a unique family of bacterial Toll/interleukin-1 receptor domain-containing proteins. Nat Med 14:399–406. [PubMed][CrossRef]
201. Snyder GA, Cirl C, Jiang J, Chen K, Waldhuber A, Smith P, Rommler F, Snyder N, Fresquez T, Durr S, Tjandra N, Miethke T, Xiao TS. 2013. Molecular mechanisms for the subversion of MyD88 signaling by TcpC from virulent uropathogenic Escherichia coli. Proc Natl Acad Sci U S A 110:6985–6990. [PubMed][CrossRef]
202. Yadav M, Zhang J, Fischer H, Huang W, Lutay N, Cirl C, Lum J, Miethke T, Svanborg C. 2010. Inhibition of TIR domain signaling by TcpC: MyD88-dependent and independent effects on Escherichia coli virulence. PLoS Pathog 6. [PubMed][CrossRef]
203. Delnay KM, Stonehill WH, Goldman H, Jukkola AF, Dmochowski RR. 1999. Bladder histological changes associated with chronic indwelling urinary catheter. J Urol 161:1106–1108; discussion 1108–1109. [PubMed][CrossRef]
204. Goble NM, Clarke T, Hammonds JC. 1989. Histological changes in the urinary bladder secondary to urethral catheterisation. Br J Urol 63:354–357. [PubMed][CrossRef]
205. Mohamed JA, Huang DB. 2007. Biofilm formation by enterococci. J Med Microbiol 56:1581–1588. [PubMed][CrossRef]
206. Guiton PS, Hung CS, Kline KA, Roth R, Kau AL, Hayes E, Heuser J, Dodson KW, Caparon MG, Hultgren SJ. 2009. Contribution of autolysin and Sortase a during Enterococcus faecalis DNA-dependent biofilm development. Infect Immun 77:3626–3638. [PubMed][CrossRef]
207. Singh KV, Nallapareddy SR, Murray BE. 2007. Importance of the ebp (endocarditis- and biofilm-associated pilus) locus in the pathogenesis of Enterococcus faecalis ascending urinary tract infection. J Infect Dis 195:1671–1677. [PubMed][CrossRef]
208. Kemp KD, Singh KV, Nallapareddy SR, Murray BE. 2007. Relative contributions of Enterococcus faecalis OG1RF sortase-encoding genes, srtA and bps (srtC), to biofilm formation and a murine model of urinary tract infection. Infect Immun 75:5399–5404. [PubMed][CrossRef]
209. Nallapareddy SR, Singh KV, Sillanpaa J, Zhao M, Murray BE. 2011. Relative contributions of Ebp Pili and the collagen adhesin ace to host extracellular matrix protein adherence and experimental urinary tract infection by Enterococcus faecalis OG1RF. Infect Immun 79:2901–2910. [PubMed][CrossRef]
210. Sillanpaa J, Nallapareddy SR, Singh KV, Prakash VP, Fothergill T, Ton-That H, Murray BE. 2010. Characterization of the ebp(fm) pilus-encoding operon of Enterococcus faecium and its role in biofilm formation and virulence in a murine model of urinary tract infection. Virulence 1:236–246. [PubMed][CrossRef]
211. Frank KL, Guiton PS, Barnes AM, Manias DA, Chuang-Smith ON, Kohler PL, Spaulding AR, Hultgren SJ, Schlievert PM, Dunny GM. 2013. AhrC and Eep are biofilm infection-associated virulence factors in Enterococcus faecalis. Infect Immun 81:1696–1708. [PubMed][CrossRef]
212. Kau AL, Martin SM, Lyon W, Hayes E, Caparon MG, Hultgren SJ. 2005. Enterococcus faecalis tropism for the kidneys in the urinary tract of C57BL/6J mice. Infect Immun 73:2461–2468. [PubMed][CrossRef]
213. Guiton PS, Hung CS, Hancock LE, Caparon MG, Hultgren SJ. 2010. Enterococcal biofilm formation and virulence in an optimized murine model of foreign body-associated urinary tract infections. Infect Immun 78:4166–4175. [PubMed][CrossRef]
214. Guiton PS, Hannan TJ, Ford B, Caparon MG, Hultgren SJ. 2013. Enterococcus faecalis overcomes foreign body-mediated inflammation to establish urinary tract infections. Infect Immun 81:329–339. [PubMed][CrossRef]
215. Nielsen HV, Guiton PS, Kline KA, Port GC, Pinkner JS, Neiers F, Normark S, Henriques-Normark B, Caparon MG, Hultgren SJ. 2012. The metal ion-dependent adhesion site motif of the Enterococcus faecalis EbpA pilin mediates pilus function in catheter-associated urinary tract infection. MBio 3. [PubMed][CrossRef]
216. Flores-Mireles AL, Pinkner JS, Caparon MG, Hultgren SJ. 2014. EbpA vaccine antibodies block binding of Enterococcus faecalis to fibrinogen to prevent catheter-associated bladder infection in mice. Sci Transl Med 6:254ra127. [PubMed][CrossRef]
217. Nielsen HV, Flores-Mireles AL, Kau AL, Kline KA, Pinkner JS, Neiers F, Normark S, Henriques-Normark B, Caparon MG, Hultgren SJ. 2013. Pilin and sortase residues critical for endocarditis- and biofilm-associated pilus biogenesis in Enterococcus faecalis. J Bacteriol 195:4484–4495. [PubMed][CrossRef]
218. Clancy KW, Melvin JA, McCafferty DG. 2010. Sortase transpeptidases: insights into mechanism, substrate specificity, and inhibition. Biopolymers 94:385–396. [PubMed][CrossRef]
219. Nallapareddy SR, Sillanpaa J, Mitchell J, Singh KV, Chowdhury SA, Weinstock GM, Sullam PM, Murray BE. 2011. Conservation of Ebp-type pilus genes among Enterococci and demonstration of their role in adherence of Enterococcus faecalis to human platelets. Infect Immun 79:2911–2920. [PubMed][CrossRef]
220. Maione D, Margarit I, Rinaudo CD, Masignani V, Mora M, Scarselli M, Tettelin H, Brettoni C, Iacobini ET, Rosini R, D’Agostino N, Miorin L, Buccato S, Mariani M, Galli G, Nogarotto R, Nardi Dei V, Vegni F, Fraser C, Mancuso G, Teti G, Madoff LC, Paoletti LC, Rappuoli R, Kasper DL, Telford JL, Grandi G. 2005. Identification of a universal Group B streptococcus vaccine by multiple genome screen. Science 309:148–150. [PubMed][CrossRef]
221. Margarit I, Rinaudo CD, Galeotti CL, Maione D, Ghezzo C, Buttazzoni E, Rosini R, Runci Y, Mora M, Buccato S, Pagani M, Tresoldi E, Berardi A, Creti R, Baker CJ, Telford JL, Grandi G. 2009. Preventing bacterial infections with pilus-based vaccines: the group B streptococcus paradigm. J Infect Dis 199:108–115. [PubMed][CrossRef]
222. Bouckaert J, Berglund J, Schembri M, De Genst E, Cools L, Wuhrer M, Hung CS, Pinkner J, Slattegard R, Zavialov A, Choudhury D, Langermann S, Hultgren SJ, Wyns L, Klemm P, Oscarson S, Knight SD, De Greve H. 2005. Receptor binding studies disclose a novel class of high-affinity inhibitors of the Escherichia coli FimH adhesin. Mol Microbiol 55:441–455. [PubMed][CrossRef]
223. Han Z, Pinkner JS, Ford B, Obermann R, Nolan W, Wildman SA, Hobbs D, Ellenberger T, Cusumano CK, Hultgren SJ, Janetka JW. 2010. Structure-based drug design and optimization of mannoside bacterial FimH antagonists. J Med Chem 53:4779–4792. [PubMed][CrossRef]
224. Wellens A, Garofalo C, Nguyen H, Van Gerven N, Slattegard R, Hernalsteens JP, Wyns L, Oscarson S, De Greve H, Hultgren S, Bouckaert J. 2008. Intervening with urinary tract infections using anti-adhesives based on the crystal structure of the FimH-oligomannose-3 complex. PLoS One 3:e2040. [PubMed][CrossRef]
225. Klein T, Abgottspon D, Wittwer M, Rabbani S, Herold J, Jiang X, Kleeb S, Luthi C, Scharenberg M, Bezencon J, Gubler E, Pang L, Smiesko M, Cutting B, Schwardt O, Ernst B. 2010. FimH antagonists for the oral treatment of urinary tract infections: from design and synthesis to in vitro and in vivo evaluation. J Med Chem 53:8627–8641. [PubMed][CrossRef]
226. Schwardt O, Rabbani S, Hartmann M, Abgottspon D, Wittwer M, Kleeb S, Zalewski A, Smiesko M, Cutting B, Ernst B. 2011. Design, synthesis and biological evaluation of mannosyl triazoles as FimH antagonists. Bioorg Med Chem 19:6454–6473. [PubMed][CrossRef]
227. Guiton PS, Cusumano CK, Kline KA, Dodson KW, Han Z, Janetka JW, Henderson JP, Caparon MG, Hultgren SJ. 2012. Combinatorial small-molecule therapy prevents uropathogenic Escherichia coli catheter-associated urinary tract infections in mice. Antimicrob Agents Chemother 56:4738–4745. [PubMed][CrossRef]
228. Totsika M, Kostakioti M, Hannan TJ, Upton M, Beatson SA, Janetka JW, Hultgren SJ, Schembri MA. 2013. A FimH Inhibitor Prevents Acute Bladder Infection and Treats Chronic Cystitis Caused by Multidrug-Resistant Uropathogenic Escherichia coli ST131. J Infect Dis 208:921–928. [PubMed][CrossRef]
229. Eden CS, Freter R, Hagberg L, Hull R, Hull S, Leffler H, Schoolnik G. 1982. Inhibition of experimental ascending urinary tract infection by an epithelial cell-surface receptor analogue. Nature 298:560–562. [PubMed][CrossRef]
230. Larsson A, Ohlsson J, Dodson KW, Hultgren SJ, Nilsson U, Kihlberg J. 2003. Quantitative studies of the binding of the class II PapG adhesin from uropathogenic Escherichia coli to oligosaccharides. Bioorg Med Chem 11:2255–2261. [PubMed][CrossRef]
231. Ohlsson J, Larsson A, Haataja S, Alajaaski J, Stenlund P, Pinkner JS, Hultgren SJ, Finne J, Kihlberg J, Nilsson UJ. 2005. Structure-activity relationships of galabioside derivatives as inhibitors of E. coli and S. suis adhesins: nanomolar inhibitors of S. suis adhesins. Org Biomol Chem 3:886–900. [PubMed][CrossRef]
232. Joosten JA, Loimaranta V, Appeldoorn CC, Haataja S, El Maate FA, Liskamp RM, Finne J, Pieters RJ. 2004. Inhibition of Streptococcus suis adhesion by dendritic galabiose compounds at low nanomolar concentration. J Med Chem 47:6499–6508. [PubMed][CrossRef]
233. Salminen A, Loimaranta V, Joosten JA, Khan AS, Hacker J, Pieters RJ, Finne J. 2007. Inhibition of P-fimbriated Escherichia coli adhesion by multivalent galabiose derivatives studied by a live-bacteria application of surface plasmon resonance. J Antimicrob Chemother 60:495–501. [PubMed][CrossRef]
234. Pieters RJ, Slotved HC, Mortensen HM, Arler L, Finne J, Haataja S, Joosten JA, Branderhorst HM, Krogfelt KA. 2013. Use of tetravalent galabiose for inhibition of streptococcus suis serotype 2 infection in a mouse model. Biology (Basel) 2:702–718. [PubMed][CrossRef]
235. Emtenas H, Ahlin K, Pinkner JS, Hultgren SJ, Almqvist F. 2002. Design and parallel solid-phase synthesis of ring-fused 2-pyridinones that target pilus biogenesis in pathogenic bacteria. J Comb Chem 4:630–639. [PubMed][CrossRef]
236. Svensson A, Larsson A, Emtenas H, Hedenstrom M, Fex T, Hultgren SJ, Pinkner JS, Almqvist F, Kihlberg J. 2001. Design and evaluation of pilicides: potential novel antibacterial agents directed against uropathogenic Escherichia coli. Chembiochem 2:915–918. [PubMed][CrossRef]
237. Pinkner JS, Remaut H, Buelens F, Miller E, Aberg V, Pemberton N, Hedenstrom M, Larsson A, Seed P, Waksman G, Hultgren SJ, Almqvist F. 2006. Rationally designed small compounds inhibit pilus biogenesis in uropathogenic bacteria. Proc Natl Acad Sci USA 103:17897–17902. [PubMed][CrossRef]
238. Hung DL, Knight SD, Woods RM, Pinkner JS, Hultgren SJ. 1996. Molecular basis of two subfamilies of immunoglobulin-like chaperones. EMBO J 15:3792–3805. [PubMed]
239. Greene SE, Pinkner JS, Chorell E, Dodson KW, Shaffer CL, Conover MS, Livny J, Hadjifrangiskou M, Almqvist F, Hultgren SJ. 2014. Pilicide ec240 disrupts virulence circuits in uropathogenic Escherichia coli. MBio 5:e02038. [PubMed][CrossRef]
240. Chapman MR, Robinson LS, Pinkner JS, Roth R, Heuser J, Hammar M, Normark S, Hultgren SJ. 2002. Role of Escherichia coli curli operons in directing amyloid fiber formation. Science 295:851–855. [PubMed][CrossRef]
241. Chorell E, Bengtsson C, Sainte-Luce Banchelin T, Das P, Uvell H, Sinha AK, Pinkner JS, Hultgren SJ, Almqvist F. 2011. Synthesis and application of a bromomethyl substituted scaffold to be used for efficient optimization of anti-virulence activity. Eur J Med Chem 46:1103–1116. [PubMed][CrossRef]
242. Chorell E, Pinkner JS, Bengtsson C, Banchelin TS, Edvinsson S, Linusson A, Hultgren SJ, Almqvist F. 2012. Mapping pilicide anti-virulence effect in Escherichia coli, a comprehensive structure-activity study. Bioorg Med Chem 20:3128–3142. [PubMed][CrossRef]
243. Chorell E, Pinkner JS, Phan G, Edvinsson S, Buelens F, Remaut H, Waksman G, Hultgren SJ, Almqvist F. 2010. Design and synthesis of C-2 substituted thiazolo and dihydrothiazolo ring-fused 2-pyridones: pilicides with increased antivirulence activity. J Med Chem 53:5690–5695. [PubMed][CrossRef]
244. Sunden F, Hakansson L, Ljunggren E, Wullt B. 2006. Bacterial interference--is deliberate colonization with Escherichia coli 83972 an alternative treatment for patients with recurrent urinary tract infection? Int J Antimicrob Agents 28(Suppl 1):S26–29. [PubMed][CrossRef]
245. Ferrieres L, Hancock V, Klemm P. 2007. Biofilm exclusion of uropathogenic bacteria by selected asymptomatic bacteriuria Escherichia coli strains. Microbiology 153:1711–1719. [PubMed][CrossRef]
246. Roos V, Ulett GC, Schembri MA, Klemm P. 2006. The asymptomatic bacteriuria Escherichia coli strain 83972 outcompetes uropathogenic E. coli strains in human urine. Infect Immun 74:615–624. [PubMed][CrossRef]
247. Klemm P, Roos V, Ulett GC, Svanborg C, Schembri MA. 2006. Molecular characterization of the Escherichia coli asymptomatic bacteriuria strain 83972: the taming of a pathogen. Infect Immun 74:781–785. [PubMed][CrossRef]
248. Sunden F, Hakansson L, Ljunggren E, Wullt B. 2010. Escherichia coli 83972 bacteriuria protects against recurrent lower urinary tract infections in patients with incomplete bladder emptying. J Urol 184:179–185. [PubMed][CrossRef]
249. Darouiche RO, Green BG, Donovan WH, Chen D, Schwartz M, Merritt J, Mendez M, Hull RA. 2011. Multicenter randomized controlled trial of bacterial interference for prevention of urinary tract infection in patients with neurogenic bladder. Urology 78:341–346. [PubMed][CrossRef]
250. Darouiche RO, Thornby JI, Cerra-Stewart C, Donovan WH, Hull RA. 2005. Bacterial interference for prevention of urinary tract infection: a prospective, randomized, placebo-controlled, double-blind pilot trial. Clin Infect Dis 41:1531–1534. [PubMed][CrossRef]
251. Koves B, Salvador E, Gronberg-Hernandez J, Zdziarski J, Wullt B, Svanborg C, Dobrindt U. 2014. Rare emergence of symptoms during long-term asymptomatic Escherichia coli 83972 carriage without an altered virulence factor repertoire. J Urol 191:519–528. [PubMed][CrossRef]
252. Rudick CN, Taylor AK, Yaggie RE, Schaeffer AJ, Klumpp DJ. 2014. Asymptomatic bacteriuria Escherichia coli are live biotherapeutics for UTI. PLoS One 9:e109321. [PubMed][CrossRef]
253. Paton AW, Morona R, Paton JC. 2000. A new biological agent for treatment of Shiga toxigenic Escherichia coli infections and dysentery in humans. Nat Med 6:265–270. [PubMed][CrossRef]
254. Watts RE, Tan CK, Ulett GC, Carey AJ, Totsika M, Idris A, Paton AW, Morona R, Paton JC, Schembri MA. 2012. Escherichia coli 83972 expressing a P fimbriae oligosaccharide receptor mimic impairs adhesion of uropathogenic E. coli. J Infect Dis doi:jis493 [pii] 10.1093/infdis/jis493.
255. Trautner BW, Cevallos ME, Li H, Riosa S, Hull RA, Hull SI, Tweardy DJ, Darouiche RO. 2008. Increased expression of type-1 fimbriae by nonpathogenic Escherichia coli 83972 results in an increased capacity for catheter adherence and bacterial interference. J Infect Dis 198:899–906. [PubMed][CrossRef]
256. Trautner BW, Darouiche RO, Hull RA, Hull S, Thornby JI. 2002. Pre-inoculation of urinary catheters with Escherichia coli 83972 inhibits catheter colonization by Enterococcus faecalis. J Urol 167:375–379. [PubMed][CrossRef]
257. Navas-Nacher EL, Dardick F, Venegas MF, Anderson BE, Schaeffer AJ, Duncan JL. 2001. Relatedness of Escherichia coli colonizing women longitudinally. Mol Urol 5:31–36. [PubMed][CrossRef]
258. Czaja CA, Stamm WE, Stapleton AE, Roberts PL, Hawn TR, Scholes D, Samadpour M, Hultgren SJ, Hooton TM. 2009. Prospective cohort study of microbial and inflammatory events immediately preceding Escherichia coli recurrent urinary tract infection in women. J Infect Dis 200:528–536. [PubMed][CrossRef]
259. Baerheim A, Larsen E, Digranes A. 1994. Vaginal application of lactobacilli in the prophylaxis of recurrent lower urinary tract infection in women. Scand J Prim Health Care 12:239–243. [PubMed][CrossRef]
260. Reid G. 2001. Probiotic agents to protect the urogenital tract against infection. Am J Clin Nutr 73:437S–443S. [PubMed]
261. Beerepoot MA, Geerlings SE, van Haarst EP, van Charante NM, ter Riet G. 2013. Nonantibiotic prophylaxis for recurrent urinary tract infections: a systematic review and meta-analysis of randomized controlled trials. J Urol 190:1981–1989. [PubMed][CrossRef]
262. Czaja CA, Stapleton AE, Yarova-Yarovaya Y, Stamm WE. 2007. Phase I trial of a Lactobacillus crispatus vaginal suppository for prevention of recurrent urinary tract infection in women. Infect Dis Obstet Gynecol 2007:35387. [PubMed][CrossRef]
263. Stapleton AE, Au-Yeung M, Hooton TM, Fredricks DN, Roberts PL, Czaja CA, Yarova-Yarovaya Y, Fiedler T, Cox M, Stamm WE. 2011. Randomized, placebo-controlled phase 2 trial of a Lactobacillus crispatus probiotic given intravaginally for prevention of recurrent urinary tract infection. Clin Infect Dis 52:1212–1217. [PubMed][CrossRef]
264. Velraeds MM, van de Belt-Gritter B, van der Mei HC, Reid G, Busscher HJ. 1998. Interference in initial adhesion of uropathogenic bacteria and yeasts to silicone rubber by a Lactobacillus acidophilus biosurfactant. J Med Microbiol 47:1081–1085. [PubMed][CrossRef]
265. Gupta K, Chou MY, Howell A, Wobbe C, Grady R, Stapleton AE. 2007. Cranberry products inhibit adherence of p-fimbriated Escherichia coli to primary cultured bladder and vaginal epithelial cells. J Urol 177:2357–2360. [PubMed][CrossRef]
266. Howell AB, Reed JD, Krueger CG, Winterbottom R, Cunningham DG, Leahy M. 2005. A-type cranberry proanthocyanidins and uropathogenic bacterial anti-adhesion activity. Phytochemistry 66:2281–2291. [PubMed][CrossRef]
267. Sobota AE. 1984. Inhibition of bacterial adherence by cranberry juice: potential use for the treatment of urinary tract infections. J Urol 131:1013–1016. [PubMed]
268. Zafriri D, Ofek I, Adar R, Pocino M, Sharon N. 1989. Inhibitory activity of cranberry juice on adherence of type 1 and type P fimbriated Escherichia coli to eucaryotic cells. Antimicrob Agents Chemother 33:92–98. [PubMed][CrossRef]
269. Di Martino P, Agniel R, David K, Templer C, Gaillard JL, Denys P, Botto H. 2006. Reduction of Escherichia coli adherence to uroepithelial bladder cells after consumption of cranberry juice: a double-blind randomized placebo-controlled cross-over trial. World J Urol 24:21–27. [PubMed][CrossRef]
270. Howell AB, Foxman B. 2002. Cranberry juice and adhesion of antibiotic-resistant uropathogens. JAMA 287:3082–3083. [PubMed][CrossRef]
271. Jepson RG, Craig JC. 2008. Cranberries for preventing urinary tract infections. Cochrane Database Syst Rev doi:10.1002/14651858.CD001321.pub4:CD001321. [PubMed][CrossRef]
272. McMurdo ME, Argo I, Phillips G, Daly F, Davey P. 2009. Cranberry or trimethoprim for the prevention of recurrent urinary tract infections? A randomized controlled trial in older women. J Antimicrob Chemother 63:389–395. [PubMed][CrossRef]
273. Stapleton AE, Dziura J, Hooton TM, Cox ME, Yarova-Yarovaya Y, Chen S, Gupta K. 2012. Recurrent urinary tract infection and urinary Escherichia coli in women ingesting cranberry juice daily: a randomized controlled trial. Mayo Clin Proc 87:143–150. [PubMed][CrossRef]
274. Barbosa-Cesnik C, Brown MB, Buxton M, Zhang L, DeBusscher J, Foxman B. 2011. Cranberry juice fails to prevent recurrent urinary tract infection: results from a randomized placebo-controlled trial. Clin Infect Dis 52:23–30. [PubMed][CrossRef]
275. Raz R, Stamm WE. 1993. A controlled trial of intravaginal estriol in postmenopausal women with recurrent urinary tract infections. N Engl J Med 329:753–756. [PubMed][CrossRef]
276. Raz R. 2011. Urinary tract infection in postmenopausal women. Korean J Urol 52:801–808. [PubMed][CrossRef]
277. Luthje P, Brauner H, Ramos NL, Ovregaard A, Glaser R, Hirschberg AL, Aspenstrom P, Brauner A. 2013. Estrogen supports urothelial defense mechanisms. Sci Transl Med 5:190ra180. [PubMed][CrossRef]
278. Curran EM, Tassell AH, Judy BM, Nowicki B, Montgomery-Rice V, Estes DM, Nowicki S. 2007. Estrogen increases menopausal host susceptibility to experimental ascending urinary-tract infection. J Infect Dis 195:680–683. [PubMed][CrossRef]
279. Wang C, Symington JW, Ma E, Cao B, Mysorekar IU. 2013. Estrogenic modulation of uropathogenic Escherichia coli infection pathogenesis in a murine menopause model. Infect Immun 81:733–739. [PubMed][CrossRef]
280. Hicks HT. 1909. Pyelitis of pregnancy treated with coli vaccine. Br Med J 1:203–204. [PubMed][CrossRef]
281. Routh CF. 1910. Vaccine treatment of pyelonephritis in pregnancy. Br Med J 1:191. [PubMed][CrossRef]
282. Hektoen L IE. 1929. Vaccine therapy: Result of a questionnaire to american physicians. JAMA: J Am Med Assoc 92:864–869. [CrossRef]
283. Benians TH. 1926. The role of vaccine therapy: in coliform infections of the urinary tract. Postgrad Med J 1:94–96. [PubMed][CrossRef]
284. Braude AI, Shapiro AP, Siemienski J. 1955. Hematogenous pyelonephritis in rats. I. Its pathogenesis when produced by a simple new method. J Clin Invest 34:1489–1497. [PubMed][CrossRef]
285. Pulendran B, Li S, Nakaya HI. 2010. Systems vaccinology. Immunity 33:516–529. [PubMed][CrossRef]
286. Pudney J, Quayle AJ, Anderson DJ. 2005. Immunological microenvironments in the human vagina and cervix: mediators of cellular immunity are concentrated in the cervical transformation zone. Biol Reprod 73:1253–1263. [PubMed][CrossRef]
287. Billips BK, Yaggie RE, Cashy JP, Schaeffer AJ, Klumpp DJ. 2009. A live-attenuated vaccine for the treatment of urinary tract infection by uropathogenic Escherichia coli. J Infect Dis 200:263–272. [PubMed][CrossRef]
288. Chan CY, St John AL, Abraham SN. 2013. Mast cell interleukin-10 drives localized tolerance in chronic bladder infection. Immunity 38:349–359. [PubMed][CrossRef]
289. Lutay N, Ambite I, Gronberg Hernandez J, Rydstrom G, Ragnarsdottir B, Puthia M, Nadeem A, Zhang J, Storm P, Dobrindt U, Wullt B, Svanborg C. 2013. Bacterial control of host gene expression through RNA polymerase II. J Clin Invest 123:2366–2379. [PubMed][CrossRef]
290. Duell BL, Carey AJ, Tan CK, Cui X, Webb RI, Totsika M, Schembri MA, Derrington P, Irving-Rodgers H, Brooks AJ, Cripps AW, Crowley M, Ulett GC. 2012. Innate Transcriptional Networks Activated in Bladder in Response to Uropathogenic Escherichia coli Drive Diverse Biological Pathways and Rapid Synthesis of IL-10 for Defense against Bacterial Urinary Tract Infection. J Immunol 188:781–792. [PubMed][CrossRef]
291. Majd M, Rushton HG, Jantausch B, Wiedermann BL. 1991. Relationship among vesicoureteral reflux, P-fimbriated Escherichia coli, and acute pyelonephritis in children with febrile urinary tract infection. J Pediatr 119:578–585. [PubMed][CrossRef]
292. Nicolle LE, Friesen D, Harding GK, Roos LL. 1996. Hospitalization for acute pyelonephritis in Manitoba, Canada, during the period from 1989 to 1992; impact of diabetes, pregnancy, and aboriginal origin. Clin Infect Dis 22:1051–1056. [PubMed][CrossRef]
293. Pennesi M, Travan L, Peratoner L, Bordugo A, Cattaneo A, Ronfani L, Minisini S, Ventura A. 2008. Is antibiotic prophylaxis in children with vesicoureteral reflux effective in preventing pyelonephritis and renal scars? A randomized, controlled trial. Pediatrics 121:e1489–1494. [PubMed][CrossRef]
294. Nagler EV, Williams G, Hodson EM, Craig JC. 2011. Interventions for primary vesicoureteric reflux. Cochrane Database Syst Rev doi:10.1002/14651858.CD001532.pub4:CD001532. [PubMed][CrossRef]
295. Schieve LA, Handler A, Hershow R, Persky V, Davis F. 1994. Urinary tract infection during pregnancy: its association with maternal morbidity and perinatal outcome. Am J Public Health 84:405–410. [PubMed][CrossRef]
296. Gilbert NM, O’Brien VP, Hultgren S, Macones G, Lewis WG, Lewis AL. 2013. Urinary tract infection as a preventable cause of pregnancy complications: opportunities, challenges, and a global call to action. Glob Adv Health Med 2:59–69. [PubMed][CrossRef]
297. Gratacos E, Torres PJ, Vila J, Alonso PL, Cararach V. 1994. Screening and treatment of asymptomatic bacteriuria in pregnancy prevent pyelonephritis. J Infect Dis 169:1390–1392. [PubMed][CrossRef]
298. Kaack MB, Roberts JA, Baskin G, Patterson GM. 1988. Maternal immunization with P fimbriae for the prevention of neonatal pyelonephritis. Infect Immun 56:1–6. [PubMed]
299. McKee AS, Munks MW, Marrack P. 2007. How do adjuvants work? Important considerations for new generation adjuvants. Immunity 27:687–690. [PubMed][CrossRef]
300. Poggio TV, La Torre JL, Scodeller EA. 2006. Intranasal immunization with a recombinant truncated FimH adhesin adjuvanted with CpG oligodeoxynucleotides protects mice against uropathogenic Escherichia coli challenge. Can J Microbiol 52:1093–1102. [PubMed][CrossRef]
301. Stanley M. 2007. Prophylactic HPV vaccines. J Clin Pathol 60:961–965. [PubMed][CrossRef]
302. Westerman LE, McClure HM, Jiang B, Almond JW, Glass RI. 2005. Serum IgG mediates mucosal immunity against rotavirus infection. Proc Natl Acad Sci U S A 102:7268–7273. [PubMed][CrossRef]
303. Levitz SM, Golenbock DT. 2012. Beyond empiricism: informing vaccine development through innate immunity research. Cell 148:1284–1292. [PubMed][CrossRef]
304. Wilson-Welder JH, Torres MP, Kipper MJ, Mallapragada SK, Wannemuehler MJ, Narasimhan B. 2009. Vaccine adjuvants: current challenges and future approaches. J Pharm Sci 98:1278–1316. [PubMed][CrossRef]
305. Gupta RK. 1998. Aluminum compounds as vaccine adjuvants. Adv Drug Deliv Rev 32:155–172. [CrossRef]
306. Petrovsky N, Aguilar JC. 2004. Vaccine adjuvants: current state and future trends. Immunol Cell Biol 82:488–496. [PubMed][CrossRef]
307. Dupuis M, Murphy TJ, Higgins D, Ugozzoli M, van Nest G, Ott G, McDonald DM. 1998. Dendritic cells internalize vaccine adjuvant after intramuscular injection. Cell Immunol 186:18–27. [PubMed][CrossRef]
308. Mosca F, Tritto E, Muzzi A, Monaci E, Bagnoli F, Iavarone C, O’Hagan D, Rappuoli R, De Gregorio E. 2008. Molecular and cellular signatures of human vaccine adjuvants. Proc Natl Acad Sci U S A 105:10501–10506. [PubMed][CrossRef]
309. Sharp FA, Ruane D, Claass B, Creagh E, Harris J, Malyala P, Singh M, O’Hagan DT, Petrilli V, Tschopp J, O’Neill LA, Lavelle EC. 2009. Uptake of particulate vaccine adjuvants by dendritic cells activates the NALP3 inflammasome. Proc Natl Acad Sci U S A 106:870–875. [PubMed][CrossRef]
310. Alving CR, Rao M, Steers NJ, Matyas GR, Mayorov AV. 2012. Liposomes containing lipid A: an effective, safe, generic adjuvant system for synthetic vaccines. Expert Rev Vaccines 11:733–744. [PubMed][CrossRef]
311. Malaviya R, Ikeda T, Abraham SN, Malaviya R. 2004. Contribution of mast cells to bacterial clearance and their proliferation during experimental cystitis induced by type 1 fimbriated E. coli. Immunol Lett 91:103–111. [PubMed][CrossRef]
312. McLachlan JB, Shelburne CP, Hart JP, Pizzo SV, Goyal R, Brooking-Dixon R, Staats HF, Abraham SN. 2008. Mast cell activators: a new class of highly effective vaccine adjuvants. Nat Med 14:536–541. [PubMed][CrossRef]
313. Shelburne CP, Nakano H, St John AL, Chan C, McLachlan JB, Gunn MD, Staats HF, Abraham SN. 2009. Mast cells augment adaptive immunity by orchestrating dendritic cell trafficking through infected tissues. Cell Host Microbe 6:331–342. [PubMed][CrossRef]
314. St John AL, Chan CY, Staats HF, Leong KW, Abraham SN. Synthetic mast-cell granules as adjuvants to promote and polarize immunity in lymph nodes. Natl Mater 11:250–257. [PubMed][CrossRef]
315. Pulendran B, Ahmed R. 2006. Translating innate immunity into immunological memory: implications for vaccine development. Cell 124:849–863. [PubMed][CrossRef]
316. Querec TD, Akondy RS, Lee EK, Cao W, Nakaya HI, Teuwen D, Pirani A, Gernert K, Deng J, Marzolf B, Kennedy K, Wu H, Bennouna S, Oluoch H, Miller J, Vencio RZ, Mulligan M, Aderem A, Ahmed R, Pulendran B. 2009. Systems biology approach predicts immunogenicity of the yellow fever vaccine in humans. Natl Immunol 10:116–125. [PubMed][CrossRef]
317. Li S, Rouphael N, Duraisingham S, Romero-Steiner S, Presnell S, Davis C, Schmidt DS, Johnson SE, Milton A, Rajam G, Kasturi S, Carlone GM, Quinn C, Chaussabel D, Palucka AK, Mulligan MJ, Ahmed R, Stephens DS, Nakaya HI, Pulendran B. 2014. Molecular signatures of antibody responses derived from a systems biology study of five human vaccines. Natl Immunol 15:195–204. [PubMed][CrossRef]
318. Brooks SJ, Lyons JM, Braude AI. 1974. Immunization against retrograde pyelonephritis. II. Prevention of retrograde Escherichia coli pyelonephritis with vaccines. Am J Pathol 74:359–364. [PubMed]
319. Kaijser B, Larsson P, Olling S. 1978. Protection against ascending Escherichia coli pyelonephritis in rats and significance of local immunity. Infect Immun 20:78–81. [PubMed]
320. Zaruba K, Vejbora O, Chobola M. 1971. The effect of preliminary sensitization and immunization on bacteriuria in rabbits with experimental pyelonephritis. Clin Exp Immunol 9:399–405. [PubMed]
321. Jensen J, Balish E, Mizutani K, Uehling DT. 1982. Resolution of induced urinary tract infection: an animal model to assess bladder immunization. J Urol 127:1220–1222. [PubMed]
322. Uehling DT, Jensen J, Balish E. 1982. Vaginal immunization against urinary tract infection. J Urol 128:1382–1384. [PubMed]
323. Uehling DT, Jensen J, Balish E. 1985. Immunization against urinary tract infections. J Urol (Paris) 91:23–26. [PubMed]
324. Uehling DT, Hopkins WJ, Jensen J, Balish E. 1987. Vaginal immunization against induced cystitis in monkeys. J Urol 137:327–329. [PubMed]
325. Roberts JA, Kaack MB, Baskin G, Svenson SB. 1995. Vaccination with a formalin-killed P-fimbriated E. coli whole-cell vaccine prevents renal scarring from pyelonephritis in the non-human primate. Vaccine 13:11–16. [PubMed][CrossRef]
326. Grischke EM, Ruttgers H. 1987. Treatment of bacterial infections of the female urinary tract by immunization of the patients. Urol Int 42:338–341. [PubMed][CrossRef]
327. Kochiashvili D, Khuskivadze A, Kochiashvili G, Koberidze G, Kvakhajelidze V. 2014. Role of the bacterial vaccine Solco-Urovac(R) in treatment and prevention of recurrent urinary tract infections of bacterial origin. Georgian Med News:11–16. [PubMed]
328. Uehling DT, James LJ, Hopkins WJ, Balish E. 1991. Immunization against urinary tract infection with a multi-valent vaginal vaccine. J Urol 146:223–226. [PubMed]
329. Uehling DT, Hopkins WJ, James LJ, Balish E. 1994. Vaginal immunization of monkeys against urinary tract infection with a multi-strain vaccine. J Urol 151:214–216. [PubMed]
330. Uehling DT, Hopkins WJ, Dahmer LA, Balish E. 1994. Phase I clinical trial of vaginal mucosal immunization for recurrent urinary tract infection. J Urol 152:2308–2311. [PubMed]
331. Hopkins WJ, Elkahwaji J, Beierle LM, Leverson GE, Uehling DT. 2007. Vaginal mucosal vaccine for recurrent urinary tract infections in women: results of a phase 2 clinical trial. J Urol 177:1349–1353; quiz 1591. [PubMed][CrossRef]
332. Uehling DT, Hopkins WJ, Balish E, Xing Y, Heisey DM. 1997. Vaginal mucosal immunization for recurrent urinary tract infection: phase II clinical trial. J Urol 157:2049–2052. [PubMed][CrossRef]
333. Uehling DT, Hopkins WJ, Beierle LM, Kryger JV, Heisey DM. 2001. Vaginal mucosal immunization for recurrent urinary tract infection: extended phase II clinical trial. J Infect Dis 183(Suppl 1):S81–83. [PubMed][CrossRef]
334. Uehling DT, Hopkins WJ, Elkahwaji JE, Schmidt DM, Leverson GE. 2003. Phase 2 clinical trial of a vaginal mucosal vaccine for urinary tract infections. J Urol 170:867–869. [PubMed][CrossRef]
335. Kruze D, Holzbecher K, Andrial M, Bossart W. 1989. Urinary antibody response after immunisation with a vaccine against urinary tract infection. Urol Res 17:361–366. [PubMed][CrossRef]
336. Russo TA, Beanan JM, Olson R, Genagon SA, MacDonald U, Cope JJ, Davidson BA, Johnston B, Johnson JR. 2007. A killed, genetically engineered derivative of a wild-type extraintestinal pathogenic E. coli strain is a vaccine candidate. Vaccine 25:3859–3870. [PubMed][CrossRef]
337. Billips BK, Forrestal SG, Rycyk MT, Johnson JR, Klumpp DJ, Schaeffer AJ. 2007. Modulation of host innate immune response in the bladder by uropathogenic Escherichia coli. Infect Immun 75:5353–5360. [PubMed][CrossRef]
338. Ochman H, Selander RK. 1984. Standard reference strains of Escherichia coli from natural populations. J Bacteriol 157:690–693. [PubMed]
339. Rudick CN, Jiang M, Yaggie RE, Pavlov VI, Done J, Heckman CJ, Whitfield C, Schaeffer AJ, Klumpp DJ. 2012. O-antigen modulates infection-induced pain states. PLoS One 7:e41273. [PubMed][CrossRef]
340. Wieser A, Romann E, Magistro G, Hoffmann C, Norenberg D, Weinert K, Schubert S. 2010. A multiepitope subunit vaccine conveys protection against extraintestinal pathogenic Escherichia coli in mice. Infect Immun 78:3432–3442. [PubMed][CrossRef]
341. Sanford JP, Hunter BW, Souda LL. 1962. The role of immunity in the pathogenesis of experimental hematogenous pyelonephritis. J Exp Med 115:383–410. [PubMed][CrossRef]
342. Uehling DT, Wolf L. 1969. Enhancement of the bladder defense mechanism by immunization. Invest Urol 6:520–526. [PubMed]
343. Roberts JA, Kaack MB, Baskin G, Svenson SB. 1993. Prevention of renal scarring from pyelonephritis in nonhuman primates by vaccination with a synthetic Escherichia coli serotype O8 oligosaccharide-protein conjugate. Infect Immun 61:5214–5218. [PubMed]
344. Kaijser B, Larsson P, Olling S, Schneerson R. 1983. Protection against acute, ascending pyelonephritis caused by Escherichia coli in rats, using isolated capsular antigen conjugated to bovine serum albumin. Infect Immun 39:142–146. [PubMed]
345. Kumar V, Ganguly N, Joshi K, Mittal R, Harjai K, Chhibber S, Sharma S. 2005. Protective efficacy and immunogenicity of Escherichia coli K13 diphtheria toxoid conjugate against experimental ascending pyelonephritis. Med Microbiol Immunol 194:211–217. [PubMed][CrossRef]
346. Stenutz R, Weintraub A, Widmalm G. 2006. The structures of Escherichia coli O-polysaccharide antigens. FEMS Microbiol Rev 30:382–403. [PubMed][CrossRef]
347. Johnson JR. 1991. Virulence factors in Escherichia coli urinary tract infection. Clin Microbiol Rev 4:80–128. [PubMed]
348. Ellis TN, Kuehn MJ. 2010. Virulence and immunomodulatory roles of bacterial outer membrane vesicles. Microbiol Mol Biol Rev 74:81–94. [PubMed][CrossRef]
349. Wurpel DJ, Moriel DG, Totsika M, Easton DM, Schembri MA. 2015. Comparative analysis of the uropathogenic Escherichia coli surface proteome by tandem mass-spectrometry of artificially induced outer membrane vesicles. J Proteomics 115:93–106. [PubMed][CrossRef]
350. Wiles TJ, Kulesus RR, Mulvey MA. 2008. Origins and virulence mechanisms of uropathogenic Escherichia coli. Exp Mol Pathol 85:11–19. [PubMed][CrossRef]
351. Oster P, Lennon D, O’Hallahan J, Mulholland K, Reid S, Martin D. 2005. MeNZB: a safe and highly immunogenic tailor-made vaccine against the New Zealand Neisseria meningitidis serogroup B disease epidemic strain. Vaccine 23:2191–2196. [PubMed][CrossRef]
352. Rosenqvist E, Hoiby EA, Wedege E, Bryn K, Kolberg J, Klem A, Ronnild E, Bjune G, Nokleby H. 1995. Human antibody responses to meningococcal outer membrane antigens after three doses of the Norwegian group B meningococcal vaccine. Infect Immun 63:4642–4652. [PubMed]
353. Sierra GV, Campa HC, Varcacel NM, Garcia IL, Izquierdo PL, Sotolongo PF, Casanueva GV, Rico CO, Rodriguez CR, Terry MH. 1991. Vaccine against group B Neisseria meningitidis: protection trial and mass vaccination results in Cuba. NIPH Ann 14:195–207; discussion 208–110.
354. Camacho AI, de Souza J, Sanchez-Gomez S, Pardo-Ros M, Irache JM, Gamazo C. 2011. Mucosal immunization with Shigella flexneri outer membrane vesicles induced protection in mice. Vaccine 29:8222–8229. [PubMed][CrossRef]
355. Roberts R, Moreno G, Bottero D, Gaillard ME, Fingermann M, Graieb A, Rumbo M, Hozbor D. 2008. Outer membrane vesicles as acellular vaccine against pertussis. Vaccine 26:4639–4646. [PubMed][CrossRef]
356. Wizemann TM, Adamou JE, Langermann S. 1999. Adhesins as targets for vaccine development. Emerg Infect Dis 5:395–403. [PubMed][CrossRef]
357. Silverblatt FJ, Cohen LS. 1979. Antipili antibody affords protection against experimental ascending pyelonephritis. J Clin Invest 64:333–336. [PubMed][CrossRef]
358. Jones CH, Pinkner JS, Nicholes AV, Slonim LN, Abraham SN, Hultgren SJ. 1993. FimC is a periplasmic PapD-like chaperone that directs assembly of type 1 pili in bacteria. Proc Natl Acad Sci U S A 90:8397–8401. [PubMed][CrossRef]
359. Asadi Karam MR, Oloomi M, Mahdavi M, Habibi M, Bouzari S. 2013. Vaccination with recombinant FimH fused with flagellin enhances cellular and humoral immunity against urinary tract infection in mice. Vaccine 31:1210–1216. [PubMed][CrossRef]
360. Karam MR, Oloomi M, Mahdavi M, Habibi M, Bouzari S. 2013. Assessment of immune responses of the flagellin (FliC) fused to FimH adhesin of Uropathogenic Escherichia coli. Mol Immunol 54:32–39. [PubMed][CrossRef]
361. Bagherpour G, Fooladi AA, Mehrabadi JF, Nourani MR, Einollahi B. 2011. Evaluation of mammalian codon usage of fimH in DNA vaccine design. Acta Microbiol Immunol Hung 58:259–271. [PubMed][CrossRef]
362. Ferraro B, Morrow MP, Hutnick NA, Shin TH, Lucke CE, Weiner DB. 2011. Clinical applications of DNA vaccines: current progress. Clin Infect Dis 53:296–302. [PubMed][CrossRef]
363. Imani Fooladi AA, Bagherpour G, Khoramabadi N, Fallah Mehrabadi J, Mahdavi M, Halabian R, Amin M, Izadi Mobarakeh J, Einollahi B. 2014. Cellular immunity survey against urinary tract infection using pVAX/fimH cassette with mammalian and wild type codon usage as a DNA vaccine. Clin Exp Vaccine Res 3:185–193. [PubMed][CrossRef]
364. Tchesnokova V, Aprikian P, Kisiela D, Gowey S, Korotkova N, Thomas W, Sokurenko E. 2011. Type 1 fimbrial adhesin FimH elicits an immune response that enhances cell adhesion of Escherichia coli. Infect Immun 79:3895–3904. [PubMed][CrossRef]
365. Pecha B, Low D, O’Hanley P. 1989. Gal-Gal pili vaccines prevent pyelonephritis by piliated Escherichia coli in a murine model. Single-component Gal-Gal pili vaccines prevent pyelonephritis by homologous and heterologous piliated E. coli strains. J Clin Invest 83:2102–2108. [PubMed][CrossRef]
366. Roberts JA, Hardaway K, Kaack B, Fussell EN, Baskin G. 1984. Prevention of pyelonephritis by immunization with P-fimbriae. J Urol 131:602–607. [PubMed]
367. Roberts JA, Kaack MB, Baskin G, Korhonen TK, Svenson SB, Winberg J. 1989. P-fimbriae vaccines. II. Cross reactive protection against pyelonephritis. Pediatr Nephrol 3:391–396. [PubMed][CrossRef]
368. Schmidt MA, O’Hanley P, Lark D, Schoolnik GK. 1988. Synthetic peptides corresponding to protective epitopes of Escherichia coli digalactoside-binding pilin prevent infection in a murine pyelonephritis model. Proc Natl Acad Sci U S A 85:1247–1251. [PubMed][CrossRef]
369. Lund B, Lindberg F, Marklund BI, Normark S. 1988. Tip proteins of pili associated with pyelonephritis: new candidates for vaccine development. Vaccine 6:110–112. [PubMed][CrossRef]
370. Schmidt G, Hacker J, Wood G, Marre R. 1989. Oral vaccination of rats with live avirulent Salmonella derivatives expressing adhesive fimbrial antigens of uropathogenic Escherichia coli. FEMS Microbiol Immunol 1:229–235. [PubMed][CrossRef]
371. Goluszko P, Goluszko E, Nowicki B, Nowicki S, Popov V, Wang HQ. 2005. Vaccination with purified Dr Fimbriae reduces mortality associated with chronic urinary tract infection due to Escherichia coli bearing Dr adhesin. Infect Immun 73:627–631. [PubMed][CrossRef]
372. He Y, Xiang Z, Mobley HL. 2010. Vaxign: the first web-based vaccine design program for reverse vaccinology and applications for vaccine development. J Biomed Biotechnol 2010:297505. [PubMed][CrossRef]
373. Alteri CJ, Hagan EC, Sivick KE, Smith SN, Mobley HL. 2009. Mucosal immunization with iron receptor antigens protects against urinary tract infection. PLoS Pathog 5:e1000586. [PubMed][CrossRef]
374. Brumbaugh AR, Smith SN, Mobley HL. 2013. Immunization with the yersiniabactin receptor, FyuA, protects against pyelonephritis in a murine model of urinary tract infection. Infect Immun 81:3309–3316. [PubMed][CrossRef]
375. Brumbaugh AR, Smith SN, Subashchandrabose S, Himpsl SD, Hazen TH, Rasko DA, Mobley HL. 2015. Blocking yersiniabactin import attenuates extraintestinal pathogenic Escherichia coli in cystitis and pyelonephritis and represents a novel target to prevent urinary tract infection. Infect Immun 83:1443–1450. [PubMed][CrossRef]
376. Moriel DG, Bertoldi I, Spagnuolo A, Marchi S, Rosini R, Nesta B, Pastorello I, Corea VA, Torricelli G, Cartocci E, Savino S, Scarselli M, Dobrindt U, Hacker J, Tettelin H, Tallon LJ, Sullivan S, Wieler LH, Ewers C, Pickard D, Dougan G, Fontana MR, Rappuoli R, Pizza M, Serino L. 2010. Identification of protective and broadly conserved vaccine antigens from the genome of extraintestinal pathogenic Escherichia coli. Proc Natl Acad Sci U S A 107:9072–9077. [PubMed][CrossRef]
377. Nesta B, Valeri M, Spagnuolo A, Rosini R, Mora M, Donato P, Alteri CJ, Del Vecchio M, Buccato S, Pezzicoli A, Bertoldi I, Buzzigoli L, Tuscano G, Falduto M, Rippa V, Ashhab Y, Bensi G, Fontana MR, Seib KL, Mobley HL, Pizza M, Soriani M, Serino L. 2014. SslE elicits functional antibodies that impair in vitro mucinase activity and in vivo colonization by both intestinal and extraintestinal Escherichia coli strains. PLoS Pathog 10:e1004124. [PubMed][CrossRef]
378. Kurupati P, Teh BK, Kumarasinghe G, Poh CL. 2006. Identification of vaccine candidate antigens of an ESBL producing Klebsiella pneumoniae clinical strain by immunoproteome analysis. Proteomics 6:836–844. [PubMed][CrossRef]
379. Moayeri N, Collins CM, O’Hanley P. 1991. Efficacy of a Proteus mirabilis outer membrane protein vaccine in preventing experimental Proteus pyelonephritis in a BALB/c mouse model. Infect Immun 59:3778–3786. [PubMed]
380. Hunter BW, Akins LL, Sanford JP. 1964. The Role of Immunity in the Pathogenesis of Experimental Retrograde Pyelonephritis. J Exp Med 119:869–879. [PubMed][CrossRef]
381. Alamuri P, Eaton KA, Himpsl SD, Smith SN, Mobley HL. 2009. Vaccination with proteus toxic agglutinin, a hemolysin-independent cytotoxin in vivo, protects against Proteus mirabilis urinary tract infection. Infect Immun 77:632–641. [PubMed][CrossRef]
382. Li X, Zhao H, Geymonat L, Bahrani F, Johnson DE, Mobley HL. 1997. Proteus mirabilis mannose-resistant, Proteus-like fimbriae: MrpG is located at the fimbrial tip and is required for fimbrial assembly. Infect Immun 65:1327–1334. [PubMed]
383. Li X, Lockatell CV, Johnson DE, Lane MC, Warren JW, Mobley HL. 2004. Development of an intranasal vaccine to prevent urinary tract infection by Proteus mirabilis. Infect Immun 72:66–75. [PubMed][CrossRef]
384. Scavone P, Miyoshi A, Rial A, Chabalgoity A, Langella P, Azevedo V, Zunino P. 2007. Intranasal immunisation with recombinant Lactococcus lactis displaying either anchored or secreted forms of Proteus mirabilis MrpA fimbrial protein confers specific immune response and induces a significant reduction of kidney bacterial colonisation in mice. Microbes Infect 9:821–828. [PubMed][CrossRef]
385. Pellegrino R, Galvalisi U, Scavone P, Sosa V, Zunino P. 2003. Evaluation of Proteus mirabilis structural fimbrial proteins as antigens against urinary tract infections. FEMS Immunol Med Microbiol 36:103–110. [PubMed][CrossRef]
386. Scavone P, Sosa V, Pellegrino R, Galvalisi U, Zunino P. 2004. Mucosal vaccination of mice with recombinant Proteus mirabilis structural fimbrial proteins. Microbes Infect 6:853–860. [PubMed][CrossRef]
387. Scavone P, Umpierrez A, Rial A, Chabalgoity JA, Zunino P. 2014. Native flagellin does not protect mice against an experimental Proteus mirabilis ascending urinary tract infection and neutralizes the protective effect of MrpA fimbrial protein. Antonie Van Leeuwenhoek 105:1139–1148. [PubMed][CrossRef]
388. Scavone P, Rial A, Umpierrez A, Chabalgoity A, Zunino P. 2009. Effects of the administration of cholera toxin as a mucosal adjuvant on the immune and protective response induced by Proteus mirabilis MrpA fimbrial protein in the urinary tract. Microbiol Immunol 53:233–240. [PubMed][CrossRef]
389. Habibi M, Asadi Karam MR, Shokrgozar MA, Oloomi M, Jafari A, Bouzari S. 2015. Intranasal immunization with fusion protein MrpH.FimH and MPL adjuvant confers protection against urinary tract infections caused by uropathogenic Escherichia coli and Proteus mirabilis. Mol Immunol 64:285–294. [PubMed][CrossRef]
390. Bauer HW, Rahlfs VW, Lauener PA, Blessmann GS. 2002. Prevention of recurrent urinary tract infections with immuno-active E. coli fractions: a meta-analysis of five placebo-controlled double-blind studies. Int J Antimicrob Agents 19:451–456. [PubMed][CrossRef]
391. Naber KG, Cho YH, Matsumoto T, Schaeffer AJ. 2009. Immunoactive prophylaxis of recurrent urinary tract infections: a meta-analysis. Int J Antimicrob Agents 33:111–119. [PubMed][CrossRef]
392. Bauer HW, Alloussi S, Egger G, Blumlein HM, Cozma G, Schulman CC. 2005. A long-term, multicenter, double-blind study of an Escherichia coli extract (OM-89) in female patients with recurrent urinary tract infections. Eur Urol 47:542–548; discussion 548. [PubMed][CrossRef]
393. Lorenzo-Gomez MF, Padilla-Fernandez B, Garcia-Criado FJ, Miron-Canelo JA, Gil-Vicente A, Nieto-Huertos A, Silva-Abuin JM. 2013. Evaluation of a therapeutic vaccine for the prevention of recurrent urinary tract infections versus prophylactic treatment with antibiotics. Int Urogynecol J 24:127–134. [PubMed][CrossRef]
394. Huber M, Ayoub M, Pfannes SD, Mittenbuhler K, Weis K, Bessler WG, Baier W. 2000. Immunostimulatory activity of the bacterial extract OM-8. Eur J Med Res 5:101–109. [PubMed]
395. Huber M, Krauter K, Winkelmann G, Bauer HW, Rahlfs VW, Lauener PA, Blessmann GS, Bessler WG. 2000. Immunostimulation by bacterial components: II. Efficacy studies and meta-analysis of the bacterial extract OM-89. Int J Immunopharmacol 22:1103–1111. [PubMed][CrossRef]
396. Lee SJ, Kim SW, Cho YH, Yoon MS. 2006. Anti-inflammatory effect of an Escherichia coli extract in a mouse model of lipopolysaccharide-induced cystitis. World J Urol 24:33–38. [PubMed][CrossRef]
397. Sedelmeier EA, Bessler WG. 1995. Biological activity of bacterial cell-wall components: immunogenicity of the bacterial extract OM-89. Immunopharmacology 29:29–36. [PubMed][CrossRef]
398. Huber M, Baier W, Serr A, Bessler WG. 2000. Immunogenicity of an E. coli extract after oral or intraperitoneal administration: induction of antibodies against pathogenic bacterial strains. Int J Immunopharmacol 22:57–68. [PubMed][CrossRef]
399. Johnson JR, O’Bryan TT, Delavari P, Kuskowski M, Stapleton A, Carlino U, Russo TA. 2001. Clonal relationships and extended virulence genotypes among Escherichia coli isolates from women with a first or recurrent episode of cystitis. J Infect Dis 183:1508–1517. [PubMed][CrossRef]
400. Kudinha T, Kong F, Johnson JR, Andrew SD, Anderson P, Gilbert GL. 2012. Multiplex PCR-based reverse line blot assay for simultaneous detection of 22 virulence genes in uropathogenic Escherichia coli. Appl Environ Microbiol 78:1198–1202. [PubMed][CrossRef]
401. Kanamaru S, Kurazono H, Ishitoya S, Terai A, Habuchi T, Nakano M, Ogawa O, Yamamoto S. 2003. Distribution and genetic association of putative uropathogenic virulence factors iroN, iha, kpsMT, ompT and usp in Escherichia coli isolated from urinary tract infections in Japan. J Urol 170:2490–2493. [PubMed][CrossRef]
402. Foxman B, Zhang L, Palin K, Tallman P, Marrs CF. 1995. Bacterial virulence characteristics of Escherichia coli isolates from first-time urinary tract infection. J Infect Dis 171:1514–1521. [PubMed][CrossRef]
403. Usein CR, Damian M, Tatu-Chitoiu D, Capusa C, Fagaras R, Tudorache D, Nica M, Le Bouguenec C. 2001. Prevalence of virulence genes in Escherichia coli strains isolated from Romanian adult urinary tract infection cases. J Cell Mol Med 5:303–310. [PubMed][CrossRef]
404. Ikaheimo R, Siitonen A, Karkkainen U, Makela PH. 1993. Virulence characteristics of Escherichia coli in nosocomial urinary tract infection. Clin Infect Dis 16:785–791. [PubMed][CrossRef]
405. Marrs CF, Zhang L, Tallman P, Manning SD, Somsel P, Raz P, Colodner R, Jantunen ME, Siitonen A, Saxen H, Foxman B. 2002. Variations in 10 putative uropathogen virulence genes among urinary, faecal and peri-urethral Escherichia coli. J Med Microbiol 51:138–142. [PubMed][CrossRef]
406. Ruiz J, Simon K, Horcajada JP, Velasco M, Barranco M, Roig G, Moreno-Martinez A, Martinez JA, Jimenez de Anta T, Mensa J, Vila J. 2002. Differences in virulence factors among clinical isolates of Escherichia coli causing cystitis and pyelonephritis in women and prostatitis in men. J Clin Microbiol 40:4445–4449. [PubMed][CrossRef]
407. Schaeffer AJ, Schwan WR, Hultgren SJ, Duncan JL. 1987. Relationship of type 1 pilus expression in Escherichia coli to ascending urinary tract infections in mice. Infect Immun 55:373–380. [PubMed]
408. Goluszko P, Moseley SL, Truong LD, Kaul A, Williford JR, Selvarangan R, Nowicki S, Nowicki B. 1997. Development of experimental model of chronic pyelonephritis with Escherichia coli O75:K5:H-bearing Dr fimbriae: mutation in the dra region prevented tubulointerstitial nephritis. J Clin Invest 99:1662–1672. [PubMed][CrossRef]
409. Smith YC, Rasmussen SB, Grande KK, Conran RM, O’Brien AD. 2008. Hemolysin of uropathogenic Escherichia coli evokes extensive shedding of the uroepithelium and hemorrhage in bladder tissue within the first 24 hours after intraurethral inoculation of mice. Infect Immun 76:2978–2990. [PubMed][CrossRef]
410. Parham NJ, Srinivasan U, Desvaux M, Foxman B, Marrs CF, Henderson IR. 2004. PicU, a second serine protease autotransporter of uropathogenic Escherichia coli. FEMS Microbiol Lett 230:73–83. [PubMed][CrossRef]
411. Russo TA, Carlino UB, Johnson JR. 2001. Identification of a new iron-regulated virulence gene, ireA, in an extraintestinal pathogenic isolate of Escherichia coli. Infect Immun 69:6209–6216. [PubMed][CrossRef]
412. Russo TA, McFadden CD, Carlino-MacDonald UB, Beanan JM, Barnard TJ, Johnson JR. 2002. IroN functions as a siderophore receptor and is a urovirulence factor in an extraintestinal pathogenic isolate of Escherichia coli. Infect Immun 70:7156–7160. [PubMed][CrossRef]
413. Lloyd AL, Henderson TA, Vigil PD, Mobley HL. 2009. Genomic islands of uropathogenic Escherichia coli contribute to virulence. J Bacteriol 191:3469–3481. [PubMed][CrossRef]
414. Starcic Erjavec M, Jesenko B, Petkovsek Z, Zgur-Bertok D. 2010. Prevalence and associations of tcpC, a gene encoding a Toll/interleukin-1 receptor domain-containing protein, among Escherichia coli urinary tract infection, skin and soft tissue infection, and commensal isolates. J Clin Microbiol 48:966–968. [PubMed][CrossRef]
415. Lloyd AL, Smith SN, Eaton KA, Mobley HL. 2009. Uropathogenic Escherichia coli Suppresses the host inflammatory response via pathogenicity island genes sisA and sisB. Infect Immun 77:5322–5333. [PubMed][CrossRef]
416. Nicholson TF, Watts KM, Hunstad DA. 2009. OmpA of uropathogenic Escherichia coli promotes postinvasion pathogenesis of cystitis. Infect Immun 77:5245–5251. [PubMed][CrossRef]
417. Zhao T, Fang XX, Liu XL, Peng L, Long M, Zhang WB, Luo J, Cao H. [Construction and functional studies of uropathogenic E. coli strains with ompT gene knockout]. Nan Fang Yi Ke Da Xue Xue Bao 32:956–959. [PubMed]
418. Hui CY, Guo Y, He QS, Peng L, Wu SC, Cao H, Huang SH. 2010. Escherichia coli outer membrane protease OmpT confers resistance to urinary cationic peptides. Microbiol Immunol 54:452–459. [PubMed][CrossRef]
419. Kruze D, Biro K, Holzbecher K, Andrial M, Bossart W. 1992. Protection by a polyvalent vaccine against challenge infection and pyelonephritis. Urol Res 20:177–181. [PubMed][CrossRef]
420. Nayir A, Emre S, Sirin A, Bulut A, Alpay H, Tanman F. 1995. The effects of vaccination with inactivated uropathogenic bacteria in recurrent urinary tract infections of children. Vaccine 13:987–990. [PubMed][CrossRef]
421. Ng TW, Akman L, Osisami M, Thanassi DG. 2004. The usher N terminus is the initial targeting site for chaperone-subunit complexes and participates in subsequent pilus biogenesis events. J Bacteriol 186:5321–5331. [PubMed][CrossRef]
422. Volkan E, Ford BA, Pinkner JS, Dodson KW, Henderson NS, Thanassi DG, Waksman G, Hultgren SJ. 2012. Domain activities of PapC usher reveal the mechanism of action of an Escherichia coli molecular machine. Proc Natl Acad Sci U S A 109:9563–9568. [PubMed][CrossRef]
423. Barnhart MM, Pinkner JS, Soto GE, Sauer FG, Langermann S, Waksman G, Frieden C, Hultgren SJ. 2000. PapD-like chaperones provide the missing information for folding of pilin proteins. Proc Natl Acad Sci U S A 97:7709–7714. [PubMed][CrossRef]
424. Verger D, Miller E, Remaut H, Waksman G, Hultgren S. 2006. Molecular mechanism of P pilus termination in uropathogenic Escherichia coli. EMBO Rep 7:1228–1232. [PubMed][CrossRef]
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/content/journal/microbiolspec/10.1128/microbiolspec.UTI-0013-2012
2016-02-05
2017-06-29

Abstract:

Urinary tract infections (UTI) are among the most common bacterial infections in humans, affecting millions of people every year. UTI cause significant morbidity in women throughout their lifespan, in infant boys, in older men, in individuals with underlying urinary tract abnormalities, and in those that require long-term urethral catheterization, such as patients with spinal cord injuries or incapacitated individuals living in nursing homes. Serious sequelae include frequent recurrences, pyelonephritis with sepsis, renal damage in young children, pre-term birth, and complications of frequent antimicrobial use including high-level antibiotic resistance and colitis. Uropathogenic (UPEC) cause the vast majority of UTI, but less common pathogens such as and other enterococci frequently take advantage of an abnormal or catheterized urinary tract to cause opportunistic infections. While antibiotic therapy has historically been very successful in controlling UTI, the high rate of recurrence remains a major problem, and many individuals suffer from chronically recurring UTI, requiring long-term prophylactic antibiotic regimens to prevent recurrent UTI. Furthermore, the global emergence of multi-drug resistant UPEC in the past ten years spotlights the need for alternative therapeutic and preventative strategies to combat UTI, including anti-infective drug therapies and vaccines. In this chapter, we review recent advances in the field of UTI pathogenesis, with an emphasis on the identification of promising drug and vaccine targets. We then discuss the development of new UTI drugs and vaccines, highlighting the challenges these approaches face and the need for a greater understanding of urinary tract mucosal immunity.

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Figures

Image of FIGURE 1
FIGURE 1

Targeting UPEC virulence factors that are critical for pathogenesis. Uropathogenic (UPEC) elaborate a variety of surface structures and two-component systems that play critical roles in UTI pathogenesis. The stages of pathogenesis, as determined from animal models and clinical data, include initial bladder colonization and the IBC cycle (), the chronic bladder outcomes of quiescent intracellular-reservoir (QIR) formation () and chronic cystitis (), and ureteral ascension and pyelitis/pyelonephritis with increased risk for bacteremia/septicemia. UPEC surface structures that play a role in UTI pathogenesis include lipopolysaccharide (LPS), polysaccharide capsule, flagella, outer-membrane vesicles, pili, non-pilus adhesins, outer-membrane proteins (OMPs), toxins, secretion systems, and TonB-dependent iron-uptake receptors, including siderophore receptors. These virulence components are attractive drug and vaccine candidates.

Source: microbiolspec February 2016 vol. 4 no. 1 doi:10.1128/microbiolspec.UTI-0013-2012
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Image of FIGURE 2
FIGURE 2

Models of pilus assembly in Gram-negative and Gram-positive pathogens. , Model of P pilus formation by the chaperone-usher pathway in uropathogenic . After secretion of pilus subunits into the periplasm via the general Sec machinery, periplasmic chaperones () serve as folding templates, providing a beta-sheet that enables proper folding of the pilin subunits into immunoglobulin-like domains, but in a non-conical orientation, in a mechanism called . Assembly and anchoring of the pilus occurs at an outer-membrane pore known as the usher (orange). The pilus-tip adhesin (red) is the first subunit to interact with the usher, via a preferential interaction between the tip adhesin/periplasmic-chaperone complex and the usher N-terminal-periplasmic domain (NTD, ), and this interaction initiates assembly by causing a conformational change in the usher that “unplugs” (Plug, ) the pore and displaces the tip-adhesin subunit/chaperone complex to two C-terminal-usher domains, CTD1 () and CTD2 () ( 50 , 421 , 422 ). The next pilin subunit/chaperone complex then binds to the NTD and if it has an N-terminal extension that is able to complete the immunoglobulin fold of the preceding subunit in a canonical fashion, this provides the free energy to displace the chaperone, in a process called , and drive assembly ( 47 49 , 423 ). In P pili, this occurs repeatedly, incorporating anywhere from hundreds to thousands of PapA major-pilin subunits (green) in the pilus, until PapH (brown) is incorporated into the pilus. PapH is a terminator because it is unable to undergo donor-strand exchange ( 424 ). Small-molecule inhibitors () that disrupt pilus assembly (“pilicides”) or adhesin binding to its receptor (“pilus-adhesin antagonists”) have been identified ( 223 , 237 ). , Model of sortase-mediated assembly of the endocarditis- and biofilm-associated pilus (Ebp pilus) in ( 217 ). Unlike CUP pili in Gram-negative bacteria, sortase-assembled pilus subunits are covalently linked. Pilin subunits are first secreted to the outside of the cell via the general Sec machinery, and are retained in the membrane via a hydrophobic domain within their cell wall-sorting sequence. Sortase C (SrtC, ) cleaves the EbpA () LPETG sequence, resulting in an EbpA-SrtC thioacyl intermediate that is resolved by the EbpC () Lys186 nucleophile. Pilus polymerization occurs when SrtC processes the EbpC LPSTG sequence at the base of a growing, membrane-associated pilus forming a pilus-SrtC intermediate that is resolved by the Lys186 of an incoming EbpC subunit. EbpB () incorporates at the base of a pilus fiber when its Lys179 nucleophile resolves a pilus-SrtC intermediate. Sortase A (SrtA, ) processing of the EbpB LPKTN sequence leads to eventual incorporation of the mature pilus into the cell wall. Sortase inhibitors () may be useful for disrupting the virulence potential of Gram-positive uropathogens.

Source: microbiolspec February 2016 vol. 4 no. 1 doi:10.1128/microbiolspec.UTI-0013-2012
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Tables

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TABLE 1

Prevalence and sites of action of selected uropathogenic (UPEC) virulence factors and their use as candidate vaccine antigens

Source: microbiolspec February 2016 vol. 4 no. 1 doi:10.1128/microbiolspec.UTI-0013-2012
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TABLE 2

Selected candidate vaccines targeting uropathogens

Source: microbiolspec February 2016 vol. 4 no. 1 doi:10.1128/microbiolspec.UTI-0013-2012